Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor, and medicinal composition containing the same

ABSTRACT

An objective of the present invention is to provide compounds having potent antitumor activity. The compounds of the present invention are represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
                         
wherein X═CH or N; Z═O or S; L=O or S; M=CR 10 R 11 , wherein R 10  and R 11 ═H, alkyl, or alkoxy, NR 12  wherein R 12 ═H or alkyl; R 1 , R 2 , and R 3 ═H or optionally substituted alkoxy; R 4 ═H; R 5-8 ═H, halogen, alkoxy or the like; and R 9 =alkyl optionally substituted by —R 14 , -T-R 15 , or —NR 16 R 17  wherein T=O, S, or NH; R 14 =an optionally substituted carbocyclic or heterocyclic ring; and R 15-17 =alkyl or an optionally substituted carbocyclic or heterocyclic ring, or —NR 18 R 19  wherein R 18  and R 19 ═H, optionally substituted alkyl, or an optionally substituted carbocylic or heterocyclic ring, or optionally substituted carbocyclic or heterocyclic ring.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to quinoline derivatives and quinazoline derivatives which have antitumor activity. More particularly, the present invention relates to quinoline derivatives and quinazoline derivatives which have inhibitory activity against the autophosphorylation of hepatocyte growth factor receptors and have inhibitory activity against abnormal cell proliferation or cell movement.

2. Background Art

Growth factors such as epithelial growth factors, platelet-derived growth factors, insulin-like growth factors, and hepatocyte growth factors (hereinafter abbreviated to “HGF”) play an important role in cell proliferation. Among others, HGF is known to be involved, as a liver regenerating factor and a kidney regenerating factor, in the regeneration of damaged liver and kidney (Oncogenesis, 3, 27 (1992)).

However, the overexpression of HGF and a receptor thereof (hereinafter abbreviated to “met”) is reported to be found in various tumors such as brain tumors, lung cancer, gastric cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cancer, and prostate cancer (Oncology Reports, 5, 1013 (1998)). In particular, in gastric cancer, excessive development of met and an increase in HGF level of serum mainly in scirrhous gastric cancers are reported (Int. J. Cancer, 55, 72, (1993)). Further, it is also known that HGF has angiogenesis activity due to the acceleration of the proliferation and migration of vascular endothelial cells (Circulation, 97, 381 (1998), and Clinical Cancer Res., 5, 3695, (1999)) and induces the dispersion and invasion of cells (J Biol Chem, 270, 27780 (1995)). For this reason, HGF-met signals are considered to be involved in the proliferation, invasion, and metastasis of various cancer cells.

NK4, a partial peptide of HGF, is reported as an HGF receptor antagonist. For example, it is reported that NK4 inhibits met phosphorylation of various cancer cells and, further, suppresses cell movement and cell invasion and has tumor growth inhibitory activity in in-vivo cancer xenograft models probably through angiogenesis inhibitory activity (Oncogene, 17, 3045 (1998), Cancer Res., 60, 6737 (2000), British J Cancer, 84, 864 (2001), and Int J Cancer, 85, 563 (2000)).

Since, however, NK4 is a peptide, the use of NK4 as a therapeutic agent requires a design regarding reliable stability in vivo, administration method and the like. On the other hand, there is no report on low toxic orally active small molecule compounds having met autophosphorylation inhibitory activity.

SUMMARY OF THE INVENTION

The present inventors have found that a certain group of quinoline derivatives and quinazoline derivatives have met autophosphorylation inhibitory activity and, at the same time, have antitumor effects.

An object of the present invention is to provide compounds having potent antitumor activity.

According to the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:

wherein

X represents CH or N;

Z represents O or S;

L represents O or S;

M represents

—C(—R¹⁰)(—R¹¹)— wherein R¹⁰ and R¹¹, which may be the same or different, represent a hydrogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, or —N(—R¹²)— wherein R¹² represents a hydrogen atom or C₁₋₄ alkyl;

R¹, R², and R³, which may be the same or different, represent

a hydrogen atom,

hydroxyl,

a halogen atom,

nitro,

amino,

C₁₋₆ alkyl,

C₂₋₆ alkenyl,

C₂₋₆ alkynyl, or

C₁₋₆ alkoxy,

in which one or two hydrogen atoms on the amino group are optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy, and

in which the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy groups are optionally substituted by hydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆ alkylcarbonyl; C₁₋₆ alkoxy carbonyl; amino on which one or two hydrogen atoms is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy;

R⁴ represents a hydrogen atom;

R⁵, R⁶, R⁷, and R⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy;

R⁹ represents

C₁₋₆ alkyl on which one or more hydrogen atoms are optionally substituted by —R¹⁴, or —NR¹⁶R¹⁷ wherein T represents —O—, —S—, or —NH—; R¹⁹ represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R¹⁵, R¹⁶, and R¹⁷, which may be the same or different, represent C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R¹⁴, R¹⁵, R¹⁶, and R¹⁷ is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,

—N(—R¹⁸)(—R¹⁹) wherein R¹⁸ and R¹⁹, which may be the same or different, represent a hydrogen atom; C₁₋₆ alkyl which is optionally substituted by C₁₋₆ alkoxy, C₁₋₆ alkylthio, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or

a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,

provided that, when X represents CH; Z represents O; L represents an oxygen atom; M represents —NH—; R¹, R⁴, R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom; and R² and R³ represent methoxy, R⁹ does not represent phenyl, ethoxy, or pyridin-2-yl.

The compound according to the present invention can be used for the treatment of malignant tumors.

DETAILED DESCRIPTION OF THE INVENTION

Compound

The terms “alkyl,” “alkoxy,” “alkenyl,” and “alkynyl” as used herein as a group or a part of a group respectively mean straight chain or branched chain alkyl, alkoxy, alkenyl, and alkynyl.

C₁₋₆ alkyl is preferably C₁₋₄ alkyl.

C₁₋₆ alkoxy is preferably C₁₋₄ alkoxy.

C₂₋₆ alkenyl is preferably C₂₋₄ alkenyl.

C₂₋₆ alkynyl is preferably C₂₋₄ alkynyl.

Examples of C₁₋₆ alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.

Examples of C₁₋₆ alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.

Examples of C₂₋₆ alkenyl include allyl, butenyl, pentenyl, and hexenyl.

Examples of C₂₋₆ alkynyl include 2-propynyl, butynyl, pentynyl, and hexynyl.

The expression “alkyl optionally substituted by” as used herein refers to alkyl, on which one or more hydrogen atoms are substituted by one or more substituents which may be the same or different, and unsubstituted alkyl. It will be understood by those skilled in the art that the maximum number of substituents may be determined depending upon the number of substitutable hydrogen atoms on the alkyl group. This applies to a group having a substituent other than the alkyl group.

The term “halogen atom” means a fluorine, chlorine, bromine, or iodine atom.

The saturated or unsaturated three- to eight-membered carbocyclic ring is preferably a four- to seven-membered, more preferably five- or six-membered, saturated or unsaturated carbocyclic ring. Examples of saturated or unsaturated three- to eight-membered carbocyclic rings include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The saturated or unsaturated three- to eight-membered heterocyclic ring contains at least one hetero-atom selected from oxygen, nitrogen, and sulfur atoms. The saturated or unsaturated three- to eight-membered heterocyclic ring preferably contains one or two hetero-atoms with the remaining ring-constituting atoms being carbon atoms. The saturated or unsaturated three- to eight-membered heterocyclic ring is preferably a saturated or unsaturated four- to seven-membered heterocyclic ring, more preferably a saturated or unsaturated five- or six-membered heterocyclic ring. Examples of saturated or unsaturated three- to eight-membered heterocyclic groups include thienyl, pyridyl, 1,2,3-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, piperazinyl, piperazino, piperidyl, piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, and azepanyl.

The saturated or unsaturated carboxylic and heterocyclic groups may condense with another saturated or heterocyclic group to form a bicyclic group, preferably a saturated or unsaturated nine- to twelve-membered bicyclic carbocyclic or heterocyclic group. Bicyclic groups include naphthyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, 1,4-benzoxanyl, indanyl, indolyl, and 1,2,3,4-tetrahydronaphthyl.

When the carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, preferably a C₁₋₃ alkylene chain. Carbocyclic or heterocyclic groups having this crosslinked structure include bicyclo[2.2.2]octanyl and norbornanyl.

R¹ preferably represents a hydrogen atom.

R² and R³ preferably represents a group other than a hydrogen atom. More preferably, R² represents unsaturated C₁₋₆ alkoxy, still further preferably methoxy, and R³ represents optionally substituted C₁₋₆ alkoxy.

The substituent of substituted C₁₋₆ alkoxy, which may be represented by R³, is preferably a halogen atom, hydroxyl, amino optionally mono- or disubstituted by optionally substituted C₁₋₆ alkyl, or optionally substituted saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, more preferably a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group. Such substituents include amino mono- or disubstituted by C₁₋₆ alkyl, phenyl, piperazinyl, piperazino, piperidyl, piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, azepanyl, imidazolyl, diazepanyl, and pyrrolidyl.

Optionally substituted alkoxy represented by R³ preferably represents —O—(CH₂)_(m)—R¹³ wherein m is an integer of 1 to 6, R¹³ is a substituent of the alkoxy group, that is, hydroxyl, a halogen atom, C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy carbonyl, optionally substituted amino, or an optionally substituted saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

Preferably, all of R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom, or alternatively any one or two of R⁵, R⁶, R⁷, and R⁸ represent a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

Carbocylic group represented by R⁹, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ and R¹⁰⁹, R¹¹⁴, R¹¹⁵, R¹¹⁶, R¹¹⁷, R¹¹⁸, R¹¹⁹, R²⁰⁹, R²¹⁴, R²¹⁵, R²¹⁶, R²¹⁷, R²¹⁸, R²¹⁹, R³¹⁹, R⁴¹⁹, and R⁵²⁰, which will be described later, and carbocylic groups on the alkyl group represented by these groups include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthyl. Preferred substituents of the carbocyclic group include a fluorine atom, a chlorine atom, methyl, and methoxy. Examples of preferred carbocyclic groups include phenyl and naphthyl.

Heterocyclic groups represented by R⁹, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ and R¹⁰⁹, R¹¹⁴, R¹¹⁵, R¹¹⁶, R¹¹⁷, R¹¹⁸, R¹¹⁹, R²⁰⁹, R²¹⁴, R²¹⁵, R²¹⁶, R²¹⁷, R²¹⁸, R²¹⁹, R³¹⁹, R⁴¹⁹, and R⁵²⁰, which will be described later, and heterocyclic groups on the alkyl group represented by these groups include thienyl, pyridyl, tetrahydropyrrolyl, indolyl, 1,2,3-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, thiomorpholino, and 1,4-benzoxanyl. Preferred substituents of the heterocyclic group include a chlorine atom, a bromine atom, and methyl. Examples of preferred heterocyclic groups include thienyl, pyridyl, isoxazolyl, and quinolyl.

The optionally substituted alkyl group represented by R⁹ preferably represents —(CH₂)p-R¹⁴, —(CH₂)p-T-R¹⁵, or —(CH₂)p-NR¹⁶R¹⁷ wherein p is an integer of 1 to 6 and R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined above.

In (—R¹⁸)(—R¹⁹) represented by R⁹, preferably, R¹⁸ represents a hydrogen atom or C₁₋₆ alkyl, and R¹⁸ represents C₁₋₆ alkyl which is optionally substituted by an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group; or an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group.

Preferred examples of R⁹ include benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, anilino, fluoroanilino, difluoroanilino, chloroanilino, methylanilino, methoxyanilino, naphthyl, thienyl-2-yl-methyl, and thienyl-3-yl-methyl.

Both R¹⁰ and R¹¹ preferably represent a hydrogen atom or alkyl, or alternatively any one of R¹⁰ and R¹¹ represents alkoxy with the other group representing a hydrogen atom.

R¹² preferably represents a hydrogen atom.

Examples of preferred compounds according to the present invention include

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents O, and M represents —N(—R¹²)—,

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents O, M represents —C(—R¹⁰)(—R¹¹)—, and

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents S, and M represents —N(—R¹²)—.

Another examples of preferred compounds according to the present invention include

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents O, M represents (—R¹²)—, R¹ and R⁴ represent a hydrogen atom, R² represents unsubstituted C₁₋₆ alkoxy, R³ represents optionally substituted C₁₋₆ alkoxy, and all of R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom or alternatively any one of R⁵, R⁶, R⁷, and R⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom,

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents O, M represents —C(—R¹⁰)(—R¹¹)—, R¹ and R⁴ represent a hydrogen atom, R² represents unsubstituted alkoxy, R³ represents optionally substituted C₁₋₆ alkoxy, and all of R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom or alternatively any one of R⁵, R⁶, R⁷, and R⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom, and

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents S, M represents —N(—R¹²)—, R¹ and R⁴ represent a hydrogen atom, R² represents unsubstituted C₁₋₆ alkoxy, R³ represents optionally substituted C₁₋₆ alkoxy, all of R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom or alternatively any one of R⁵, R⁶, R⁷, and R⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

Examples of preferred compounds according to the present invention include compounds represented by formula (100):

wherein

R¹⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy,

R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸, which may be the same or different, represents a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and

R¹⁰⁹ represents

C₁₋₆ alkyl on which one or more hydrogen atoms are optionally substituted by —R¹¹⁴, -T-R¹¹⁵, or —NR¹¹⁶R¹¹⁷ in which T represents —O—, —S—, or —NH—; R¹¹⁴ represents saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R¹¹⁵ represents C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R¹¹⁶ and R¹¹⁷, which may be the same or different, represent C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R¹¹⁴, R¹¹⁵, R¹¹⁶, and R¹¹⁷ is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group or

a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxycarbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-carbocyclic or heterocyclic group.

Preferably, all of R¹⁰⁵, R¹⁰⁶, R¹⁰⁷ and R¹⁰⁸ represent a hydrogen atom or alternatively any one of R¹⁰⁵, R¹⁰⁶, R¹⁰⁷ and R¹⁰⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

In formula (100), the optionally substituted alkyl group represented by R¹⁰⁹ preferably represents —(CH₂)p-R¹¹⁴, wherein p is an —(CH₂)p-T-R¹¹⁵, or —(CH₂)p-NR¹¹⁶R¹¹⁷ integer of 1 to 6 and R¹¹⁴, R¹¹⁵, R¹¹⁶, and R¹¹⁷ are as defined above.

In —N(—R¹¹⁸)(—R¹¹⁹) represented by R¹⁰⁹, preferably, R¹¹⁸ represents a hydrogen atom or C₁₋₆ alkyl, and R¹¹⁹ represents C₁₋₆ alkyl which is optionally substituted by an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group; or an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group.

Preferred examples of R¹⁰⁹ include benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, naphthyl, and thienyl.

Examples of preferred compounds according to the present invention include compounds of formula (200):

wherein

R²⁰³ represents hydroxyl or C₁₋₂ alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy,

R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and

R²⁰⁹ represents

C₁₋₆ alkyl on which one or more hydrogen atoms are optionally substituted by —R²¹⁴, -T-R²¹⁵, or —NR²¹⁶R²¹⁷ wherein T represents —O—, —S—, or —NH—; R²¹⁴ represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R²¹⁵ represents C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R²¹⁶ and R²¹⁷, which may be the same or different, represent C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R²¹⁴, R²¹⁵, R²¹⁶, and R²¹⁷ is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or

a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

Preferably, all of R²⁰⁵, R²⁰⁶, R²⁰⁷, and R²⁰⁸ represent a hydrogen atom, or alternatively any one of R²⁰⁵, R²⁰⁶, R²⁰⁷, and R²⁰⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

In formula (200), preferably, the optionally substituted alkyl group represented by R²⁰⁹ represents —(CH₂)p-R²¹⁴, —(CH₂)p-T-R²¹⁵, or —(CH₂)p-NR²¹⁶R²¹⁷ wherein p is an integer of 1 to 6, R²¹⁴, R²¹⁵, R²¹⁶, and R²¹⁷ are as defined above.

In —N(—R²¹⁸)(—R²¹⁹) represented by R²⁰⁹, preferably, R²¹⁸ represents a hydrogen atom or C₁₋₆ alkyl, and R²¹⁹ represents C₁₋₆ alkyl which is optionally substituted by an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group; or an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group.

Preferred examples of R²⁰⁹ include benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl, and methoxybenzyl.

Examples of preferred compounds according to the present invention include compounds represented by formula (300):

wherein

R³⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substituted by a halogen atom or a saturated or unsaturated six-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy,

R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy,

R³¹⁰ and R³¹¹ represent a hydrogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy,

R³¹⁸ represents a hydrogen atom or C₁₋₄ alkyl,

R³¹⁹ represents

C₁₋₄ alkyl which is optionally substituted by a saturated or unsaturated six-membered carbocyclic group which is optionally substituted by C₁₋₆ alkyl; C₁₋₆ alkoxy; a halogen atom; nitro; trifluoromethyl; C₁₋₆ alkoxy carbonyl; cyano; cyano C₁₋₆ alkyl; C₁₋₆ alkylthio; phenoxy; acetyl; or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or

a saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the four- to seven-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the four- to seven-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

Preferably, all of R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸ represent a hydrogen atom, or alternatively any one of R³⁰⁵, R³⁰⁶ R³⁰⁷, and R³⁰⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

Preferred examples of R³¹⁹ include phenyl, fluorophenyl, difluorophenyl, chlorophenyl, methylphenyl, and methoxyphenyl.

Examples of preferred compounds according to the present invention include compounds represented by formula (400):

wherein

R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷, and R⁴⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy,

R⁴¹⁹ represents an unsaturated five- or six-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the five- or six-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the five- or six-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

Preferably, all of R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷ and R⁴⁰⁸ represent a hydrogen atom, or alternatively any one of R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷ and R⁴⁰⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

Preferred examples of R⁴¹⁹ include phenyl, fluorophenyl, difluorophenyl, chlorophenyl, methylphenyl, methoxyphenyl, pyridyl, isoxazolyl, and quinolyl.

Examples of preferred compounds according to the present invention include compounds represented by formula (500):

wherein

X represents CH or N,

when L represents O and M represents —N(—R¹²)—, Q represents CH₂ or NH,

when L represents O and M represents —C(—R¹⁰)(—R¹¹)—, Q represents NH,

when L represents S and M represents —N(—R¹²) —, Q represents CH₂,

R⁵⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy,

R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, and R⁵⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and

R⁵²⁰ represents a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, or a halogen atom.

Preferably, all of R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, and R⁵⁰⁸ represent a hydrogen atom, or alternatively any one of R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, and R⁵⁰⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

Examples of preferred compounds according to the present invention are as follows. The number attached to the compound represents the number of the corresponding working example described below.

-   (1)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-N1-phenylacetylthiourea; -   (2)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-N′-[2-(4-fluorophenyl)acetyl]thiourea; -   (3)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-N′-[2-(4-fluorophenyl)acetyl]urea; -   (4) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenyl-acetylurea; -   (5)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(4-fluorophenyl)malonamide; -   (6)     N-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-N′-(2,4-difluorophenyl)malonamide; -   (7)     1-(2-cyclopentylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; -   (8)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(2,3-dihydro-1H-1-indol-1-yl)acetyl]-urea; -   (9)     N-phenyl-({[4-(6,7-dimethoxyquinolin-4-yloxy)-anilino]carbonyl}amino)methanamide; -   (10)     N-(4-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (11)     1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; -   (12)     1-(3-fluoro-4-{6-methoxy-7-[4-(4-methyl-piperazin-1-yl)-butoxy]quinolin-4-yloxy}phenyl)-3-phenylacetylurea; -   (13)     1-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; -   (14)     1-{4-[7-(3-chloro-propoxy)-6-methoxyquinolin-4-yloxy]-3-fluorophenyl}-3-phenylacetylurea; -   (15)     N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2-methylmalonamide; -   (16)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-phenylacetylurea; -   (17)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-phenylacetylurea; -   (18)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylurea; -   (19)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)urea; -   (20)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)urea; -   (21)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-thiophen-3-ylacetyl)urea; -   (22)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-fluorophenyl)acetyl]urea; -   (23)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(4-fluorophenyl)acetyl]urea; -   (24)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-fluorophenyl)acetyl]urea; -   (25)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-fluorophenyl)acetyl]urea; -   (26)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]urea; -   (27)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2-fluorophenyl)acetyl]urea; -   (28)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(2-fluorophenyl)acetyl]urea; -   (29)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiophen-2-ylacetyl)urea; -   (30)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-thiophen-2-ylacetyl)urea; -   (31)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(2-thiophen-2-ylacetyl)urea; -   (32)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-thiophen-2-ylacetyl)urea; -   (33)     1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; -   (34)     1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; -   (35)     1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; -   (36)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]urea; -   (37)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]urea; -   (38)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenyl]-3-[2-(4-fluorophenyl)acetyl]urea; -   (39)     1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; -   (40)     1-[4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(4-fluorophenyl)acetyl]urea; -   (41)     1-{3-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; -   (42)     1-{3-fluoro-4-[6-methoxy-7-(4-piperidine-1-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; -   (43)     1-(3-fluoro-4-{6-methoxy-7-[4-(4-methyl-piperazin-1-yl)-butoxy]quinolin-4-yloxy}phenyl)-3-[2-(4-fluorophenyl)acetyl]urea; -   (44)     1-{2-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; -   (45)     1-{2-fluoro-4-[6-methoxy-7-(4-piperidine-1-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; -   (46)     1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; -   (47)     1-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; -   (48)     1-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; -   (49)     1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]quinolin-4-yloxy}phenyl)-3-[2-(4-fluorophenyl)acetyl]urea; -   (50)     1-{2-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; -   (51)     1-(2-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]quinolin-4-yloxy}phenyl)-3-[2-(4-fluorophenyl)acetyl]urea; -   (52)     1-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; -   (53)     1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]quinolin-4-yloxy}phenyl)-3-phenylacetylurea; -   (54)     1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; -   (55)     1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; -   (56)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(naphthalene-1-carbonyl)thiourea; -   (57)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(naphthalene-1-carbonyl)thiourea; -   (58)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-phenylacetylthiourea; -   (59)     1-[2-(2-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; -   (60)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenylacetylthiourea; -   (61)     1-(2-cyclohexylacetyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]thiourea; -   (62)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-ethoxypropionyl)thiourea; -   (63)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylthiourea; -   (64)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(3-o-tolylpropionyl)thiourea; -   (65)     1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylthiourea; -   (66)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiophen-2-ylacetyl)thiourea; -   (67)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-methyl-phenyl]-3-phenylacetylthiourea; -   (68)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-methoxyphenyl]-3-phenylacetylthiourea; -   (69)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenyl]-3-phenylacetylthiourea; -   (70)     1-[3,5-dichloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenylacetylthiourea; -   (71)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea; -   (72)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea; -   (73)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea; -   (74)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea; -   (75)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea; -   (76)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea; -   (77)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-m-tolylacetyl)thiourea; -   (78)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-m-tolylacetyl)thiourea; -   (79)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-o-tolylacetyl)thiourea; -   (80)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea; -   (81)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea; -   (82)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-p-tolylacetyl)thiourea; -   (83)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea; -   (84)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(2-o-tolylacetyl)thiourea; -   (85)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)thiourea; -   (86)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenyl]-3-(2-thiophen-3-ylacetyl)thiourea; -   (87)     1-[2-(2-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (88)     1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; -   (89)     1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; -   (90)     1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (91)     1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; -   (92)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-p-tolylacetyl)thiourea; -   (93)     1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (94)     1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (95)     1-[2-(2,6-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (96)     1-[2-(2,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (97)     1-[2-(2,6-dichlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (98)     N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]malonamide; -   (99)     N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]malonamide; -   (100)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-phenylmalonamide; -   (101)     N-cycloheptyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide; -   (102)     N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide; -   (103)     N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2-methoxymalonamide; -   (104)     N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2,2-dimethylmalonamide; -   (105)     N-(4-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (106)     1-[3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl]-3-phenylacetylurea; -   (107)     1-(2-chloro-benzoyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]urea; -   (108)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-methyl-benzoyl)urea; -   (109)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-pentanoylurea; -   (110)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-diethylaminoacetyl)urea; -   (111)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-pyrrolidin-1-ylacetyl)urea; -   (112)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(isopropylmethylamino)acetyl]urea; -   (113)     1-(2-cyclohexylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; -   (114)     1-(2-cyclohexylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; -   (115)     1-(2-cyclohexylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; -   (116)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-cyclopentylsulfanylacetyl)urea; -   (117)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-o-tolylaminoacetyl)urea; -   (118)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiophen-3-ylacetyl)urea; -   (119)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)acetyl]urea; -   (120)     1-[2-(4-benzyl-piperidin-1-yl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; -   (121)     1-[2-(2,3-dihydro-1H-1-indol-1-yl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; -   (122)     1-[2-(2,3-dihydro-1H-1-indol-1-yl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; -   (123)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-[1,2,3]triazol-1-ylacetyl)urea; -   (124)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-p-tolylacetyl)urea; -   (125)     1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; -   (126)     1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; -   (127)     1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; -   (128)     1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; -   (129)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylsulfanylacetyl)urea; -   (130)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(1-methyl-1H-imidazol-2-ylsulfanyl)-acetyl]urea; -   (131)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiomorpholin-4-ylacetyl)urea; -   (132)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiomorpholin-4-ylacetyl)urea; -   (133)     1-[2-(2,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; -   (134)     1-[2-(2,6-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; -   (135)     1-[2-(2,6-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; -   (136)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]urea; -   (137)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]urea; -   (138)     1-[2-(2,3-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; -   (139)     1-[2-(2,3-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; -   (140)     1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; -   (141)     1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; -   (142)     1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; -   (143)     1-cyclopentanecarbonyl-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (144)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-methoxybenzoyl)thiourea; -   (145)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-trifluoromethyl-benzoyl)thiourea; -   (146)     1-(2-bromobenzoyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (147)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-methylsulfanylpropionyl)thiourea; -   (148)     1-(4-chloro-butyryl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (149)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-o-tolylacetyl)thiourea; -   (150)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylcyclopropanecarbonyl)thiourea; -   (151)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea; -   (152)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea; -   (153)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea; -   (154)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea; -   (155)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-nitrophenyl)acetyl]thiourea; -   (156)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-nitrophenyl)acetyl]thiourea; -   (157)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenoxyacetyl)thiourea; -   (158)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylpropionyl)thiourea; -   (159)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-ethoxypropionyl)thiourea; -   (160)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(5-methylthiophen-2-carbonyl)thiourea; -   (161)     1-(3-cyclopentylpropionyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; -   (162)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methylphenyl]-3-phenylacetylthiourea; -   (163)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2,5-dimethylphenyl]-3-phenylacetylthiourea; -   (164)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea; -   (165)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-ethoxypropionyl)thiourea; -   (166)     1-(2-cyclohexylacetyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (167)     1-(2-butoxyacetyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (168)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-p-tolylacetyl)thiourea; -   (169)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea; -   (170)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-o-tolylacetyl)thiourea; -   (171)     1-[2-(3-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; -   (172)     1-[2-(3-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (173)     1-[2-(3-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (174)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-chlorophenyl)acetyl]thiourea; -   (175)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-m-tolylacetyl)thiourea; -   (176)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(2-m-tolylacetyl)thiourea; -   (177)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(5-methyl-hexanoyl)thiourea; -   (178)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(5-methyl-hexanoyl)thiourea; -   (179)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(5-methyl-hexanoyl)thiourea; -   (180)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-methoxy-propionyl)thiourea; -   (181)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea; -   (182)     1-[2-(2-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (183)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-chlorophenyl)acetyl]thiourea; -   (184)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea; -   (185)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea; -   (186)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea; -   (187)     1-[2-(4-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; -   (188)     1-[2-(4-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (189)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-chlorophenyl)acetyl]thiourea; -   (190)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(2-p-tolylacetyl)thiourea; -   (191)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(4-methyl-cyclohexyl)acetyl]thiourea; -   (192)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(4-methyl-cyclohexyl)acetyl]thiourea; -   (193)     1-(2-butoxyacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; -   (194)     1-[2-(2,3-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (195)     1-[2-(2,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (196)     1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (197)     1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (198)     1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (199)     1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; -   (200)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]-thiourea; -   (201)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]-thiourea; -   (202)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(3-trifluoromethylphenyl)acetyl]-thiourea; -   (203)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(3-trifluoromethylphenyl)acetyl]-thiourea; -   (204)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]thiourea; -   (205)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]-thiourea; -   (206)     1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]-thiourea; -   (207)     1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]-thiourea; -   (208)     1-[2-(2,6-dichlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; -   (209)     N-butyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide; -   (210)     N-(3-chlorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide; -   (211)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(2-methoxyphenyl)malonamide; -   (212)     N-cyclobutyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide; -   (213) methyl     3-{2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenylcarbamoyl]acetylamino}benzoate; -   (214)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(1-phenylethyl)malonamide; -   (215)     N-benzyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide; -   (216)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-methyl-N′-phenylmalonamide; -   (217)     N-cyclohexyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide; -   (218)     N-cyclohexylmethyl-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide; -   (219)     N-(4-chlorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide; -   (220)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(3-hydroxyphenyl)malonamide; -   (221)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(3,3-dimethyl-butyl)malonamide; -   (222)     N-[2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(2,4-difluorophenyl)malonamide; -   (223)     N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methylphenyl]malonamide; -   (224)     N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2,5-dimethylphenyl]malonamide; -   (225)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-2-methyl-N′-phenylmalonamide; -   (226)     N-cyclohexyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-2-methylmalonamide; -   (227)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-pyridin-3-ylmalonamide; -   (228)     N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-2,2-dimethyl-N′-phenylmalonamide; -   (229)     N-(2,4-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (230)     N-(3-bromo-5-methyl-2-pyridyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (231)     N-(5-chloro-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (232)     N-(5-methyl-3-isoxazolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (233)     N-(3-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (234)     N-(6-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (235)     N-(5-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (236)     N-(2-pyridyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (237)     N-(1-methyl-1H-5-pyrazolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (238)     N-(2,3-dihydro-1,4-benzodioxin-6-yl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (239)     N-(3-cyanophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (240)     N-[2-(trifluoromethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methan-amide; -   (241)     N-[4-(cyanomethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (242)     N-(4-chloro-2-methylphenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (243)     N-(2,3-dihydro-1H-5-indenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (244)     N-(3-methoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (245) methyl     2-({({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)carbonyl}amino)benzoate; -   (246)     N-(2-benzylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (247)     N-(2-bromophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (248)     N-(2-chlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (249)     N-(4-chlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (250)     N-(2-chloro-4-fluorophenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (251)     N-(3-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (252)     N-(2-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (253)     N-[2-(methylsulfanyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (254)     N-(4-nitrophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (255)     N-(2-phenoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (256)     N-(3-methylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (257)     N-(4-methylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (258)     N-(2,6-dimethylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (259)     N-[2-(1H-1-pyrrolyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (260)     N-(8-quinolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (261)     N-(3-acetylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (262)     N-(5-quinolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (263)     N-(2,6-dichlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (264)     N-(3,4-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (265)     N-(2,6-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (266)     N-(2-methoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; -   (267)     N-[2-(2-hydroxyethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; -   (268)     N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-N′-phenylacetyl-thiourea; -   (269)     N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-N′-(4-fluorophenyl)-malonamide; -   (270)     1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea; -   (271)     1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; -   (272)     1-{4-[7-(2-diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-phenylacetylthio-urea; -   (273)     1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-[1,4]diazepan-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea; -   (275)     1-{4-[7-(2-diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; -   (276)     1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea; -   (277)     1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; -   (278)     1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; -   (279)     1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; -   (282)     1-(3-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; -   (283)     1-(3-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetylurea; -   (284)     1-(3-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea; -   (285)     1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-thiourea; -   (286)     1-{2-fluoro-4-[(6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea; -   (287)     1-{2-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenyl-acetyl-urea; -   (288)     1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; -   (289)     1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; -   (291)     1-{4-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-phenylacetyl-urea; -   (292)     1-{3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-urea; -   (293)     1-{4-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea; -   (294)     1-{3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea; -   (295)     1-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea; -   (296)     1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-[2-(2-fluoro-phenyl)-acetyl]-urea; -   (297)     1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-(2-m-toluoyl-acetyl)-thiourea; -   (298)     1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; -   (299)     1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; -   (300)     1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea; -   (301)     1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea; -   (302)     1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea; -   (303)     1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea; -   (304)     1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-thiourea; -   (305)     1-{3-fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-urea; -   (306)     1-{3-fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea; -   (307)     1-{3-fluoro-4-[(7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea; -   (308)     1-(3-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-urea; -   (309) (4-hydroxymethyl-phenyl)-3-phenylacetyl-thiourea; -   (310)     1-(3-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; -   (311)     1-(2-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-urea; -   (312)     1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea; -   (313)     1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; -   (314)     1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; -   (315)     1-{(3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; -   (316)     1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; -   (317)     1-[2-(2-chloro-phenyl)-acetyl]-3-{(3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; -   (318)     1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; -   (319)     1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; -   (320)     1-[2-(3-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; -   (321)     1-[2-(3-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; -   (322)     1-[2-(3-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; -   (323)     1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; -   (324)     1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; -   (325)     1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; -   (326)     1-[2-(4-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; -   (327)     1-[2-(4-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; -   (328)     1-[2-(4-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; -   (329)     1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; -   (330)     1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; -   (331)     1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-thiourea; -   (332)     1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-thiourea; -   (333)     1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-O—     toluoyl-acetyl)-thiourea; -   (334)     1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea; -   (335)     1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-thiourea; -   (336)     1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea;     and -   (337)     1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-urea.

Examples of particularly preferred compounds according to the present invention include compounds 1 to 6, 9 to 13, 16 to 39, 42, 43, 49, 52 to 54, 56 to 102, 105, 106, 266 to 269, 285, 286, 288, 312, 313, 333, and 334.

Examples of most preferred compounds according to the present invention include compounds 1, 2, 3, 11, and 268.

The compounds according to the present invention may form pharmaceutically acceptable salts thereof. Preferred examples of such salts include: alkali metal or alkaline earth metal salts such as sodium salts, potassium salts or calcium salts; hydrohalogenic acid salts such as hydrofluoride salts, hydrochloride salts, hydrobromide salts, or hydroiodide salts; inorganic acid salts such as nitric acid salts, perchloric acid salts, sulfuric acid salts, or phosphoric acid salts; lower alkylsulfonic acid salts such as methanesulfonic acid salts, trifluoromethanesulfonic acid salts, or ethanesulfonic acid salts; arylsulfonic acid salts such as benzenesulfonic acid salts or p-toluenesulfonic acid salts; organic acid salts such as fumaric acid salts, succinic acid salts, citric acid salts, tartaric acid salts, oxalic acid salts, maleic acid salts, acetic acid salts, malic acid salts, lactic acid salts, or ascorbic acid salts; and amino acid salts such as glycine salts, phenylalanine salts, glutamic acid salts, or aspartic acid salts.

The compounds according to the present invention may form solvates. Such solvates include, for example, hydrates, alcoholates, for example, methanolates and ethanolates, and etherates, for example, diethyl etherate.

Production of Compounds

Compounds according to the present invention may be produced, for example, according to schemes 1 to 9. Starting compounds necessary for the synthesis of the compounds according to the present invention are commercially available or alternatively can be easily produced by conventional methods. In the schemes, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁸, R¹⁹, and X are as defined above; PG represents a protective group; R³′O represents optionally substituted alkoxy; Hal represents a halogen atom; R⁵¹ and R⁵², which may be the same or different, represent optionally substituted C₁₋₆ alkyl, or alternatively R⁵¹ and R⁵² may combine to form a saturated or unsaturated three- to eight-membered heterocylic ring together with a nitrogen atom attached thereto; and n is an integer of 1 to 6.

For example, a 4-chloroquinoline derivative can be synthesized by a conventional method as described, for example, in Org. Synth. Col. Vol. 3, 272 (1955), Acta Chim. Hung., 112, 241 (1983), or WO 98/47873. Scheme 1 shows an example of the synthesis of the 4-chloroquinoline derivative. A quinolone derivative is produced by reacting a 2-aminoacetophenone derivative with a formic ester, for example, ethyl formate, in a suitable solvent, for example, tetrahydrofuran, in the presence of a base, for example, sodium methoxide. The 4-chloroquinoline derivative is produced by reacting the quinolone derivative in the presence of a chlorinating agent, for example, phosphorus oxychloride.

For example, a 4-chloroquinazoline derivative may be produced as follows. A quinazolone derivative is produced by reacting a 2-aminobenzoic acid derivative with formamide in a suitable solvent, for example, a mixed solvent composed of N,N-dimethylformamide and methanol, in the presence of a base, for example, sodium methoxide. The 4-chloroquinazoline derivative is produced by reacting the quinazolone derivative in the presence of a chlorinating agent, for example, phosphorus oxychloride.

Next, a 4-(aminophenoxy)quinoline derivative or a corresponding quinazoline derivative is produced by reacting a nitrophenol derivative with the 4-chloroquinoline derivative or corresponding quinazoline derivative in a suitable solvent, for example, chlorobenzene, to synthesize a 4-(nitrophenoxy)quinoline derivative or a corresponding quinazoline derivative and then reacting the 4-(nitrophenoxy)quinoline derivative or corresponding quinazoline derivative in a suitable solvent, for example, N,N-dimethyl formamide, in the presence of a catalyst, for example, palladium hydroxide-carbon, palladium-carbon, under a hydrogen atmosphere. The nitro group can also be reduced with zinc, iron or the like.

Alternatively, the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative may be produced by reacting an aminophenol derivative with the 4-chloroquinoline derivative or corresponding quinazoline derivative in a suitable solvent, for example, dimethyl sulfoxide, in the presence of a base, for example, sodium hydride. Alternatively, the 4-(aminophenoxy)quinazoline derivative may also be produced by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the solution to a two-phase reaction with a solution of the 4-chloroquinazoline derivative in a suitable organic solvent, for example, ethyl methyl ketone, in the presence of a phase transfer catalyst, for example, tetra-n-butylammonium chloride, or in the absence of the catalyst.

A carbonylthiourea derivative is produced by reacting a 4-(aminophenoxy)quinoline derivative or a quinazoline derivative with a carbonyl thioisocyanate derivative in a suitable solvent, for example, a mixed solvent composed of toluene and ethanol. The carbonyl thioisocyanate derivative is commercially available or can be easily produced by a conventional method. For example, the carbonyl thioisocyanate derivative is produced by reacting an acid chloride derivative with potassium thiocyanate in a suitable solvent, for example, acetonitrile.

A carbonylurea derivative is produced by reacting a 4-(aminophenoxy)quinoline derivative or a quinazoline derivative with a carbonyl isocyanate derivative in a suitable solvent, for example, N,N-dimethylformamide. The carbonyl isocyanate derivative is commercially available or can be easily produced by a conventional method. For example, as described in J. Org. Chem., 30, 4306 (1965), the carbonyl isocyanate derivative is produced by reacting an amide derivative with oxalyl chloride in a suitable solvent, for example, 1,2-dichloroethane.

An aminocarbonylurea derivative is produced by reacting a 4-(aminophenoxy)quinoline derivative or a quinazoline derivative with N-(chlorocarbonyl) isocyanate in a suitable solvent, for example, dichloromethane, in the presence of a base, for example, diisopropylamine and then reacting the product with an amine derivative.

An amide derivative is produced by reacting a 4-(aminophenoxy)quinoline derivative or a quinazoline derivative with a carboxylic acid derivative or a metal salt thereof in a suitable solvent, for example, in chloroform, in the presence of a condensing agent, for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and a carboxylic acid activating agent, for example, 1-hydroxybenzotriazole monohydrate.

For example, a derivative having a specific substituent at the 7-position of the quinoline ring can be produced according to scheme 3. A nitro group can be introduced by protecting a commercially available 4′-hydroxyacetophenone derivative with a suitable substituent, for example, benzyl, and then reacting the protected 4′-hydroxyacetophenone derivative with a nitrating agent, for example, fuming nitric acid-acetic acid. The later steps are carried out as shown in scheme 1. Specifically, the nitro group is reduced to an amino group which is then reacted with a formic ester in the presence of a base to give a quinolone ring. Next, the quinolone ring is reacted with a chlorinating agent to give a 4-chloroquinoline derivative. In the chlorination reaction, when phosphorus oxychloride is used as the chlorinating agent, the yield can be improved by adding a base, for example, N,N-diisopropylethylamine. Next, a 4-(aminophenoxy)quinoline derivative is produced by reacting the nitrophenol derivative with a 4-chloroquinoline derivative to synthesize a 4-(nitrophenoxy)quinoline derivative which is then reacted in a suitable solvent in a hydrogen atmosphere in the presence of a catalyst. The nitro group can also be reduced with zinc, iron or the like. Alternatively, the 4-(aminophenoxy)quinoline derivative may be produced by reacting an aminophenol derivative with a 4-chloroquinoline derivative in the presence of a base.

For example, a derivative having a specific substituent at the 7-position of the quinazoline ring can be produced according to scheme 4. A nitro group can be introduced by protecting a hydroxyl group in a commercially available 4′-hydroxybenzoic acid ester derivative with a suitable substituent, for example, benzyl, and then reacting the product with a nitrating agent, for example, fuming nitric acid-acetic acid. Later steps are carried out as shown in scheme 1. Specifically, a quinazolone ring is formed by reducing the nitro group to an amino group and then reacting the product with formamide in the presence of a base. Next, a 4-chloroquinazoline derivative can be produced by reacting the product with a chlorinating agent. In the chlorination reaction, when phosphorus oxychloride is used as a chlorinating agent, the addition of a base, for example, N,N-diisopropylethylamine can improve the yield. Next, a 4-(aminophenoxy)quinazoline derivative is produced by reacting the nitrophenol derivative with a 4-chloroquinazoline derivative to synthesize a 4-(nitrophenoxy)quinazoline derivative which is then reacted in a suitable solvent in a hydrogen atmosphere in the presence of a catalyst. The nitro group can also be reduced with zinc, iron or the like. The 4-(aminophenoxy)quinazoline derivative may also be produced by reacting an aminophenol derivative with a 4-chloroquinazoline derivative in the presence of a base. Alternatively, the 4-(aminophenoxy)quinazoline derivative may be produced by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the solution to a two-phase reaction with a solution of the 4-chloroquinazoline derivative in an organic solvent in the presence of a phase transfer catalyst or in the absence of the catalyst.

For example, a carbonylthiourea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be produced according to scheme 5. Specifically, a 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative is produced by removing the protective group of the hydroxyl group in the 4-(nitrophenoxy)quinoline derivative or quinazoline derivative produced in scheme 3 or 4 under suitable conditions. For example, when the protective group is benzyl, for example, the deprotection reaction is carried out in N,N-dimethylformamide in a hydrogen atmosphere in the presence of palladium hydroxide-carbon or palladium-carbon. Next, a 4-((aminophenoxy)quinoline derivative or a corresponding quinazoline derivative is produced by alkylating the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative under suitable conditions, for example, by reacting the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative with an alkyl halide in a suitable solvent in the presence of a base and then reacting the alkylation product in a suitable solvent, for example, N,N-dimethylformamide, in a hydrogen atmosphere in the presence of a catalyst, for example, palladium hydroxide-carbon or palladium-carbon. The nitro group can also be reduced with zinc, iron or the like. Later steps are carried out as shown in scheme 2. Specifically, a carbonylthiourea derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with a carbonylthio isocyanate derivative in a suitable solvent.

For example, a carbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be produced according to scheme 6. Specifically, the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative, of which the 7-position has been alkylated in scheme 5, is reacted as shown in scheme 2. More specifically, a carbonylurea derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or quinazoline derivative with a carbonyl isocyanate derivative in a suitable solvent. The carbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can also be synthesized by other methods. At the outset, the 4-(aminophenoxy)quinoline derivative or quinazoline derivative produced in scheme 3 or 4 is reacted as shown in scheme 2. Specifically, a carbonylurea derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with a carbonyl isocyanate derivative in a suitable solvent. A 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative is produced by removing the protective group of the hydroxyl group in the carbonylurea derivative under suitable conditions. For example, when the protective group is benzyl, for example, the deprotection reaction is carried out in a hydrogen atmosphere in N,N-dimethylformamide in the presence of palladium hydroxide-carbon or palladium-carbon. Next, a carbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring is produced by alkylating the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative under suitable conditions, for example, by reacting the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative with an alkyl halide in a suitable solvent in the presence of a base.

For example, an aminocarbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be produced according to scheme 7. Specifically, the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative, of which the 7-position has been alkylated, prepared in scheme 5 is reacted as shown in scheme 2. That is, an aminocarbonylurea derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with N-(chlorocarbonyl)isocyanate in a suitable solvent in the presence of a base and then reacting the product with an amine derivative. The aminocarbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can also be synthesized by other methods. At the outset, the 4-(aminophenoxy)quinoline derivative or quinazoline derivative produced in scheme 3 or 4 is reacted as shown in scheme 2. Specifically, an aminocarbonylurea derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with N-(chlorocarbonyl)isocyanate in a suitable solvent in the presence of a base and then reacting the product with an amine derivative. A 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative is produced by removing the protective group of the hydroxyl group in the aminocarbonylurea derivative under suitable conditions. For example, when the protective group is benzyl, the deprotection reaction is carried out, for example, in N,N-dimethylformamide, in a hydrogen atmosphere in the presence of palladium hydroxide-carbon or palladium-carbon. Next, an aminocarbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring is produced by alkylating the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative under suitable conditions, for example, with an alkyl halide in a suitable solvent in the presence of a base.

For example, an amide derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be produced according to scheme 8. Specifically, the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative, of which the 7-position has been alkylated, prepared in scheme 5 is reacted as shown in scheme 2. That is, an amide derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with a carboxylic acid derivative or a metal salt thereof in a suitable solvent in the presence of a condensing agent and a carboxylic acid activating agent. The amide derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can also be synthesized by other methods. At the outset, the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative produced in scheme 3 or 4 is reacted as shown in scheme 2. That is, an amide derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with a carboxylic acid derivative or a metal salt thereof in a suitable solvent in the presence of a condensing agent and a carboxylic acid activating agent. A 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative is produced by removing the protective group of the hydroxyl group in the amide derivative under suitable conditions. For example, when the protective group is benzyl, the deprotection reaction is carried out, for example, in N,N-dimethylformamide, in a hydrogen atmosphere in the presence of palladium hydroxide-carbon or palladium-carbon. Next, an amide derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring is produced by alkylating the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative under suitable conditions, for example, by reacting the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative with an alkyl halide in a suitable solvent in the presence of a base.

For example, a carbonylurea derivative and carbonylthiourea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be produced according to scheme 9. Specifically, a carbonylurea derivative or a carbonylthiourea derivative can be produced by deprotecting the 4-aminophenoxyquinoline derivative or corresponding quinazoline derivative, of which the 7-position has been protected by benzyl, under acidic conditions to give a phenol compound, then reacting the phenol compound with an alkyl halide in a suitable solvent in the presence of a base to give a corresponding ether compound, and then reacting the product with a suitable amine in a suitable solvent in the presence of a base to give a corresponding 7-amino-substituted (4-aminophenoxy)quinoline derivative and then reacting this derivative with a carbonyl isocyanate derivative or a carbonylisothiocyanate derivative. Alternatively, a corresponding carbonylthiourea derivative having a specific substituent at the 7-position can be produced by reacting the ether compound, provided after the reaction with the alkyl halide, with a carbonylisothiocyanate derivative to give a carbonylthiourea derivative and then reacting the carbonylthiourea derivative with a suitable amine in a suitable solvent in the presence of a base.

Use of Compounds/Pharmaceutical Composition

The compounds according to the present invention have tumor growth inhibitory activity in vivo (see Pharmacological Test Examples 3, 4, and 5).

Further, the compounds according to the present invention inhibit in vitro the met autophosphorylation caused by the stimulation of human epidermal cancer cells A431 with HGF and the met autophosphorylation which constantly occurs in gastric cancer cells MKN45 non-dependently upon HGF (see Pharmacological Test Examples 1 and 2).

Upon HGF stimulation or in a HGF-non-dependent manner for certain cancer cells, met accelerates proliferation and motility in various cell species through the autophosphorylation of intracellular region with tyrosine kinase (J. Biochem., 119, 591, (1996), Jpn. J. Cancer Res., 88, 564, (1997), and Int. J. Cancer, 78, 750, (1998)). In particular, in a plurality of cancers, for example, the increasing of HGF concentration in the blood, excessive development of met, and the development of met mutants which have acquired HGF non-dependency are reported. met signals are considered to be involved in the proliferation and invasion of various cancer cells and metastasis (Int. J. Cancer, 55, 72, (1993), Oncology Reports, 5, 1013 (1998), Proc. Natl. Acad. Sci. USA, 88, 4892, (1991), and Cancer, 88, 1801, (2000)). Further, it is also reported that HGF accelerates through met the proliferation and migration activity of vascular endothelial cells and accelerates angiogenesis (Circulation, 97, 381 (1998) and Clinical Cancer Res., 5, 3695, (1999)), and, consequently, it is estimated that HGF is also related to angiogenesis in cancers.

Accordingly, the compounds according to the present invention can inhibit the growth, invasion, metastasis, and angiogenesis of cancer cells and thus can be used in the treatment of malignant tumors.

According to the present invention, there is provided a pharmaceutical composition comprising the compound according to the present invention. The pharmaceutical composition according to the present invention can be used in the treatment of malignant tumors such as brain tumors, gastric cancer, colon cancer, pancreatic cancer, lung cancer, renal cancer, ovarian cancer, and prostate cancer.

Further, according to the present invention, there is provided a method for treating a malignant tumor, comprising the step of administering a therapeutically effective amount of the compound according to the present invention together with a pharmaceutically acceptable carrier to a mammal including a human.

Furthermore, according to the present invention, there is provided use of the compound according to the present invention, for the manufacture of a medicament for use in the treatment of a malignant tumor.

The compounds according to the present invention can be administered to human and non-human animals orally or parenterally by administration routes, for example, intravenous administration, intramuscular administration, subcutaneous administration, rectal administration, or percutaneous administration. Therefore, the pharmaceutical composition comprising as an active ingredient the compound according to the present invention is formulated into suitable dosage forms according to the administration routes. Specifically, oral preparations include tablets, capsules, powders, granules, and syrups, and parental preparations include injections, suppositories, tapes, and ointments.

These various preparations may be prepared by conventional methods, for example, with commonly used excipients, disintegrants, binders, lubricants, colorants, and diluents.

Excipients include, for example, lactose, glucose, corn starch, sorbit, and crystalline cellulose. Disintegrants include, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, and dextrin. Binders include, for example, dimethylcellulose, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, and polyvinyl pyrrolidone. Lubricants include, for example, talc, magnesium stearate, polyethylene glycol, and hydrogenated vegetable oils.

In preparing the injections, if necessary, for example, buffers, pH adjustors, stabilizers, tonicity agents, and preservatives may be added.

The content of the compound according to the present invention in the pharmaceutical composition according to the present invention may vary depending upon the dosage form. In general, however, the content is 0.5 to 50% by weight, preferably 1 to 20% by weight, based on the whole composition.

The dose may be appropriately determined in consideration of, for example, the age, weight, sex, difference in diseases, and severity of condition of individual patients, preferably in the range of 1 to 100 mg/kg. This dose is administered at a time daily or divided doses of several times daily.

The compound according to the present invention may be administered in combination with other medicament, for example, a carcinostatic agent. In this case, the compound according to the present invention may be administered simultaneously with or after or before the administration of other medicament. The type, administration intervals and the like of the carcinostatic agent may be determined depending upon the type of cancer and the condition of patients.

EXAMPLES

The present invention is further illustrated by Examples that are not intended as a limitation of the invention.

Starting compounds necessary for synthesis were produced as described in WO 97/17329, WO 98/47873, WO 00/43366, and Japanese Patent Laid-Open Publication No. 328782/1997. Starting compounds not described in these publications were produced as described in Production Examples below.

Production Example 1 Starting Compound 1

7-(Benzyloxy)-4-chloro-6-methoxyquinoline (29 g), 3-fluoro-4-nitrophenol (20 g), N,N-diisopropylethylamine (33 ml), and chlorobenzene (14 ml) were added, and the mixture was stirred with heating at 140° C. for 15 hr. After the completion of the reaction, a 2 N aqueous sodium hydroxide solution (30 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give the target compound (40 g, yield 50%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.58 (d, J=5.1 Hz, 1H), 8.48-8.44 (m, 1H), 8.21-8.19 (m, 1H), 7.64-7.35 (m, 8H), 6.79 (d, J=5.1 Hz, 1H), 5.33 (s, 2H), 3.94 (s, 3H)

Mass spectrometric value (m/z): 421 [M+H]⁺

Production Example 2 Starting Compound 2

7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline (35 g), zinc (74 g), and ammonium chloride (14 g) were added to ethanol/water (20/1, 525 ml), and the mixture was stirred with heating at 120° C. for 18 hr. After the completion of the reaction, the reaction solution was filtered through Celite. The filtrate was concentrated, and the concentrate was washed with water to give the target compound (32 g, yield 94%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.58 (d, J=5.1 Hz, 1H), 8.48-8.44 (m, 1H), 8.24 (m, 2H), 7.64-7.38 (m, 9H), 6.75 (d, J=5.1 Hz, 1H), 5.31 (s, 2H), 3.94 (s, 3H)

Mass spectrometric value (m/z): 391 [M+H]⁺

Production Example 3 Starting Compound 3

4-Fluorophenylacetamide (78 mg, see Example 3 for the production process thereof) was dissolved in 1,2-dichloroethane (20 ml) to prepare a solution. Oxalyl chloride (56 μl) was then added to the solution, and the mixture was heated under reflux at 110° C. for 15.5 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. Dimethylformamide (10 ml) and 4-{[7-(benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-fluoroaniline (50 mg) were added to the crude, and the mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude which was then purified by chromatography on silica gel using chloroform/methanol for development to give the target compound (49 mg, yield 67%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.16 (br, 1H), 10.75 (br, 1H), 8.49 (d, J=4.9 Hz, 1H), 8.24-8.19 (m, 1H), 7.53-7.35 (m, 10H), 7.19-7.11 (m, 3H), 6.56 (d, J=5.4 Hz, 1H), 5.31 (s, 2H), 3.94 (s, 3H), 3.75 (s, 2H)

Mass spectrometric value (m/z): 570 [M+H]⁺

Production Example 4 Starting Compound 4

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-fluorophenyl)-N′-[2-(4-fluorophenyl)acetyl]urea (1.6 g) and palladium hydroxide-carbon (1.3 g) were added to dimethylformamide (14 ml), and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 hr. After the completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated to give the target compound (1.3 g, yield 98%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.39 (m, 2H), 8.21-8.18 (m, 1H), 7.45 (m, 1H), 7.33-7.23 (m, 8H), 7.01 (m, 1H), 6.42 (m, 1H), 6.18 (m, 2H), 3.92 (s, 3H)

Mass spectrometric value (m/z): 480 [M+H]⁺

Production Example 5 Starting Compound 5

7-(Benzyloxy)-4-chloro-6-methoxyquinoline (81 g), 2-fluoro-4-nitrophenol (51 g), N,N-diisopropylethylamine (94 ml), and chlorobenzene (40 ml) were added, and the mixture was stirred with heating at 140° C. for 18 hr. After the completion of the reaction, a 2 N aqueous sodium hydroxide solution (40 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give the target compound (100 g, yield 92%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.45 (d, J=5.4 Hz, 1H), 7.53-7.34 (m, 7H), 7.07-7.03 (m, 1H), 6.89-6.82 (m, 2H), 6.43 (d, J=5.4 Hz, 1H), 5.29 (s, 2H), 3.94 (s, 3H)

Mass spectrometric value (m/z): 421 [M+H]⁺

Production Example 6 Starting Compound 6

7-(Benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (36 g), zinc (74 g), and ammonium chloride (14 g) were added to ethanol/water (20/1, 525 ml), and the mixture was stirred with heating at 120° C. for 19 hr. After the completion of the reaction, the reaction solution was filtered through Celite. The filtrate was concentrated, and the concentrate was washed with water to give the target compound (35 g, yield 96%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.57 (d, J=5.1 Hz, 1H), 8.44-8.37 (m, 1H), 8.22 (m, 2H), 7.65-7.38 (m, 9H), 6.78 (d, J=5.1 Hz, 1H), 5.33 (s, 2H), 3.96 (s, 3H)

Mass spectrometric value (m/z): 391 [M+H]⁺

Production Example 7 Starting Compound 7

4-Fluorophenylacetamide (86 mg, see Example 3 for the production process thereof) was dissolved in 1,2-dichloroethane (200 ml) at 80° C. to prepare a solution. Oxalyl chloride (150 μl) was added to the solution, and the mixture was stirred at 80° C. for 10 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. Dimethylformamide (2 ml) and 4-{[7-(benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluoroaniline (170 mg) were added to the crude, and the mixture was stirred at room temperature for 3 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give 248 mg of the target compound.

¹H-NMR (CDCl₃, 400 MHz): δ 8.46 (d, J=5.1 Hz, 1H), 7.50-6.85 (m, 16H), 6.44 (d, J=5.2 Hz, 1H), 5.31 (s, 2H), 3.93 (s, 3H), 3.74 (s, 2H)

Mass spectrometric value (m/z): 570 [M+H]⁺

Production Example 8 Starting Compound 8

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluorophenyl)-N′-[2-(4-fluorophenyl)acetyl]urea (1.5 g) and palladium hydroxide-carbon (1.1 g) were added to dimethylformamide (20 ml), and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 hr. After the completion of the reaction, the reaction solution was filtered through Celite. The filtrate was concentrated to give the target compound (1.1 g, yield 88%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.51 (d, J=5.2 Hz, 1H), 7.89-7.70 (m, 1H), 7.51-7.07 (m, 11H), 6.31 (d, J=5.1 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 2H)

Mass spectrometric value (m/z): 480 [M+H]⁺

Production Example 9 Starting Compound 9

2-Phenylacetamide (76 mg) was dissolved in 1,2-dichloroethane (200 ml) at 80° C. to prepare a solution. Oxalyl chloride (150 μl) was added to the solution, and the mixture was stirred at 80° C. for 10 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. Dimethylformamide (2 ml) and 4-{[7-(benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluoroaniline (170 mg) were added to the crude which was then stirred at room temperature for 3 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give 228 mg of the target compound.

¹H-NMR (CDCl₃, 400 MHz): δ 8.43 (d, J=5.3 Hz, 1H), 7.55-7.19 (m, 17H), 6.42 (d, J=5.4 Hz, 1H), 5.31 (s, 2H), 3.95 (s, 3H), 3.75 (s, 2H)

Mass spectrometric value (m/z): 552 [M+H]⁺

Production Example 10 Starting Compound 10

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluorophenyl)-N′-(2-phenylacetyl)urea (1.2 g) and palladium hydroxide-carbon (1.0 g) were added to dimethylformamide (20 ml), and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 hr. After the completion of the reaction, the reaction solution was filtered through Celite. The filtrate was concentrated to give the target compound (0.85 g, yield 85%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.43 (d, J=5.1 Hz, 1H), 7.82-7.79 (m, 1H), 7.49-7.08 (m, 12H), 6.36 (d, J=5.1 Hz, 1H), 3.95 (s, 3H), 3.75 (s, 2H)

Mass spectrometric value (m/z): 462 [M+H]⁺

Production Example 11 Starting Compound 11

3-Fluoro-4-[(7-benzyloxy-6-methoxy-4-quinolyl)oxy]-nitrobenzene (2.5 g), together with trifluoroacetic acid (15 ml) and methanesulfonic acid (0.7 ml), was heated under reflux for one hr. The solvent was removed by evaporation, and the residue was then neutralized with a 10% aqueous sodium hydroxide solution. The precipitated crystal was collected by suction filtration to give a crude crystal (1.95 g). The crude crystal was dissolved in dimethylformamide (50 ml) without purification. Potassium carbonate (4.3 g) and 1-bromo-3-chloropropane (4.9 g) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was extracted with ethyl acetate, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give a crude which was then washed with an ethyl acetate/hexane (1/1) mixed solution to give the target compound (1.76 g, yield 73%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.35-2.41 (m, 2H), 3.80 (t, J=6.3 Hz, 2H), 3.99 (s, 3H), 4.34 (t, J=6.3 Hz, 2H), 6.53 (d, J=5.1 Hz, 1H), 7.27-7.34 (m, 1H), 7.42 (s, 1H), 7.46 (s, 1H), 8.10-8.18 (m, 2H), 8.56 (d, J=5.1 Hz, 1H)

Production Example 12 Starting Compound 12

3-Fluoro-4-{[7-(3-chloropropyl)-6-methoxy-4-quinolyl]oxy}nitrobenzene (500 mg) was dissolved in dimethylformamide (20 ml) to prepare a solution. Potassium carbonate (890 mg), sodium iodide (290 mg), and morpholine (645 mg) were added to the solution, and the mixture was stirred at 70° C. for 18 hr. The mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give a crude. The crude was dissolved in methanol (30 ml) without purification. Ammonium chloride (207 mg) and zinc (1.26 g) were added to the solution, and the mixture was heated under reflux for 5 hr. Zinc was removed by filtration. Chloroform was added to the filtrate, the mixture was washed with a saturated sodium hydrogencarbonate solution, and the solvent was then removed by evaporation under the reduced pressure to give a crude. The crude was purified by column chromatography on silica gel using chloroform/methanol for development to give the target compound (440 mg, yield 80%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.02-2.11 (m, 2H), 2.35-2.47 (m, 4H), 2.50 (t, J=6.3 Hz, 2H), 3.61-3.69 (m, 4H), 3.75 (s, 2H), 3.96 (s, 3H), 4.20 (t, J=6.6 Hz, 2H), 6.33 (d, J=5.4 Hz, 1H), 6.41-6.51 (m, 2H), 6.96 (t, J=8.5 Hz, 1H), 7.35 (s, 1H), 7.51 (s, 1H), 8.39 (d, J=5.4 Hz, 1H)

Example 1

Phenylacetyl chloride [starting compound B] (1.89 ml) and potassium thiocyanate (2.09 g) were dissolved in acetonitrile (15 ml) to prepare a solution, and the solution was then stirred at 80° C. for one hr. Water was added to the reaction solution, the mixture was extracted with chloroform, and chloroform was then removed by evaporation under the reduced pressure to give a crude. The crude was dissolved in toluene/ethanol (1/1). 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline [starting compound A] (3.03 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solvent was removed by evaporation under the reduced pressure. The residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (0.69 g, yield 14.5%.

¹H-NMR (CDCl₃, 400 MHz): δ 3.76 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.46 (d, J=4.4 Hz, 1H), 7.23-7.34 (m, 3H), 7.38-7.48 (m, 5H), 7.56 (s, 1H), 7.93 (m, 1H), 8.48 (br, 1H), 8.51 (d, J=5.4 Hz, 1H), 12.47 (br, 1H)

Mass spectrometric value (m/z): 492 [M+H]⁺

Example 2

Thionyl chloride (348 μl) was added to 4-fluorophenylacetic acid [starting compound B] (123 mg), and the mixture was stirred with heating at 50° C. for one hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. The crude was dissolved in acetonitrile (20 ml). Potassium thiocyanate (155 mg) was added to the solution, and the mixture was stirred with heating at 50° C. for 40 min. Thereafter, 4-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluoroaniline [starting compound A] (50 mg) was added thereto, and the mixture was then further stirred with heating for 60 min. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. An aqueous saturated sodium hydrogencarbonate solution was added to the crude, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and was concentrated under the reduced pressure. The concentrate was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.87 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.45 (d, J=5.1 Hz, 1H), 7.12 (m, 2H), 7.23-7.32 (m, 3H), 7.40 (m, 1H), 7.44 (s, 1H), 7.56 (s, 1H), 7.93 (m, 1H), 8.51 (d, J=5.1 Hz, 1H), 8.70 (br, 1H), 12.45 (br, 1H)

Mass spectrometric value (m/z): 510 [M+H]⁺

Example 3

4-Fluorophenylacetic acid [starting compound B] (15 g) was dissolved in thionyl chloride (15 ml) to prepare a solution which was then heated at 60° C. for one hr. Excess thionyl chloride was removed by evaporation under the reduced pressure to give 4-fluorophenylacetyl chloride. The acid chloride was dissolved in acetone (200 ml). Ammonium acetate (112 g) was added to the solution, and the mixture was stirred at room temperature for 17 hr. An aqueous saturated sodium hydrogencarbonate solution (150 ml) was added thereto, and the mixture was stirred at room temperature for one hr. The reaction solution was then extracted with chloroform, and the solvent in the extract was removed by evaporation to give a crude crystal. The resultant crude crystal was washed with a hexane/ethyl acetate (2/1) mixed solution to give 4-fluorophenylacetamide (10.5 g, yield 70%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.53 (s, 2H), 5.25-5.70 (m, 2H), 7.00-7.05 (m, 2H), 7.20-7.26 (m, 2H)

4-Fluorophenylacetamide (2.05 g) was dissolved in 1,2-dichloroethane (250 ml) to prepare a solution. Oxalyl chloride (1.63 ml) was then added to the solution, and the mixture was heated for 15.5 hr under reflux. The solvent was removed by evaporation under the reduced pressure to give a crude. The crude was then dissolved in dimethylformamide (50 ml) to prepare a solution which was then added at room temperature to a previously prepared solution of 4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-fluoroaniline [starting compound A] (2.10 g) in dimethylformamide (30 ml). The mixture was stirred at that temperature for 5 hr. The solvent was removed by evaporation under the reduced pressure to give a crude. The crude was purified by column chromatography on silica gel using chloroform/methanol for development. The solvent was removed by evaporation under the reduced pressure to give a crude compound which was then washed with methanol to give the title compound (2.27 g, yield 69%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.74 (s, 2H), 4.04 (s, 3H), 4.05 (s, 3H), 6.52 (d, J=5.4 Hz, 1H), 6.99 (m, 2H), 7.10 (m, 2H), 7.30 (m, 2H), 7.45 (s, 1H), 7.49 (s, 1H), 8.17-8.24 (m, 2H), 8.52 (d, J=5.4 Hz, 1H), 10.73 (br, 1H)

Mass spectrometric value (m/z): 494 [M+H]⁺

Example 4

2-Phenylacetamide [starting compound B] (91 mg) was dissolved in 1,2-dichloroethane (250 ml) to prepare a solution. Oxalyl chloride (73 μl) was added to the solution, and the mixture was heated under reflux at 110° C. for 15.5 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. Dimethylformamide (10 ml) and 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (50 mg) were added to the crude, and the mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. The crude was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (44 mg, yield 57%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 10.96 (s, 1H), 10.52 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.30 (s, 1H), 7.64 (d, J=9.0 Hz, 2H), 7.49 (s, 1H), 7.43-6.84 (m, 7H), 6.44 (d, J=5.4 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.72 (s, 2H)

Mass spectrometric value (m/z): 458 [M+H]⁺

Example 5

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (5.00 g) was dissolved in chloroform (100 ml) to prepare a solution. Potassium carbonate (4.66 g) was added to the solution, and the mixture was stirred at 0° C. Methylmalonyl chloride [starting compound B] (2.18 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 60 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The dried chloroform layer was then concentrated under the reduced pressure to give a crude. The crude was then dissolved in ethanol/water (10/1, 165 ml). Lithium hydroxide monohydrate (1.42 g) was added to the solution, and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated under the reduced pressure. Water was then added to the concentrate, and the solution was made weakly acidic by the addition of hydrochloric acid. The solution was allowed to stand overnight at 0° C., followed by filtration to give 6.45 g of a crystal (hereinafter referred to simply as “carboxylic acid”). The carboxylic acid (30 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (30 mg), 1-hydroxybenzotriazole monohydrate (24 mg), and 4-fluoroaniline [starting compound C] (10 mg) were dissolved in chloroform (3 ml) to prepare a solution which was then stirred at 60° C. overnight. The reaction solution was developed on diatomaceous earth impregnated with an aqueous saturated sodium hydrogencarbonate solution, followed by extraction with chloroform. The solvent in the extract was removed by evaporation to give a crude. The crude was purified by HPLC using chloroform/methanol for development to give the title compound (0.7 mg, yield 1.9%).

¹H-NMR (CDCl₃/CD₃OD, 400 MHz): δ 3.49 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.46 (d, J=5.1 Hz, 1H), 7.01-7.08 (m, 2H), 7.15-7.19 (m, 2H), 7.41 (s, 1H), 7.52-7.56 (m, 3H), 7.66-7.70 (m, 2H), 8.46 (d, J=5.4 Hz, 1H)

Mass spectrometric value (m/z): 476 [M+H]⁺

Example 6

2,4-Difluoroaniline [starting compound C] (3.0 g) was dissolved in chloroform (50 ml) to prepare a solution. Potassium carbonate (6.24 g) was added to the solution, and the mixture was stirred. Ethylmalonyl chloride [starting compound B] (4 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 10 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The dried chloroform layer was concentrated under the reduced pressure to give 5.12 g of a crude. In ethanol/water (10/1, 33 ml) was dissolved 2.85 g out of 5.12 g of the crude. Lithium hydroxide monohydrate (0.99 g) was added to the solution, and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated under the reduced pressure to give 3.76 g of a crude (hereinafter referred to simply as “carboxylic acid”). Chloroform (3 ml) was added to 3-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (32 mg), carboxylic acid (31 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28 mg), and 1-hydroxybenzotriazole monohydrate (22 mg), and the mixture was stirred at 60° C. overnight. The reaction solution was developed on diatomaceous earth impregnated with an aqueous saturated sodium hydrogencarbonate solution, followed by extraction with chloroform. The solvent in the extract was removed by evaporation to give a crude. The crude was purified by HPLC using chloroform/methanol for development to give the title compound (0.1 mg, yield 2.0%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.59 (s, 2H), 4.05 (s, 3H), 4.07 (s, 3H), 6.33 (d, J=5.1 Hz, 1H), 6.90-7.33 (m, 4H), 7.45 (s, 1H), 7.52 (s, 1H), 7.58 (s, 1H), 7.90-7.93 (m, 1H), 8.48 (d, J=5.4 Hz, 1H)

Mass spectrometric value (m/z): 528 [M+H]⁺

Example 7

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (100 mg) was dissolved in chloroform (3 ml) to prepare a solution. Chloroacetyl isocyanate [starting compound B] (40 mg) was added to the solution, and the mixture was stirred at room temperature for 10 hr. The reaction solution was purified by chromatography on silica gel to give N-(2-chloroacetyl)-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (116 mg, yield 83%). Next, N-(2-chloroacetyl)-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (50 mg) and potassium carbonate (26 mg) were added to chloroform, and cyclopentanethiol [starting compound C] (38 μl) was added to the mixture with stirring. The mixture was stirred at room temperature for 3 hr, and the reaction solution was filtered through Celite. The filtrate was then concentrated under the reduced pressure to give a crude. The crude was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (35 mg, yield 60%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 10.84 (br, 1H), 10.49 (br, 1H), 8.48 (d, J=5.1 Hz, 1H), 7.69-7.67 (m, 4H), 7.51 (s, 1H), 7.39 (s, 1H), 7.26-7.24 (d, J=9.0 Hz, 1H), 3.93 (s, 6H), 3.41 (s, 2H), 2.08-1.97 (m, 2H), 1.67-1.42 (m, 7H)

Mass spectrometric value (m/z): 482 [M+H]⁺

Example 8

3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (100 mg) was dissolved in chloroform (3 ml) to prepare a solution. Chloroacetyl isocyanate [starting compound B] (42 mg) was added to the solution, and the mixture was stirred at room temperature for 10 hr. The reaction solution was purified by chromatography on silica gel to give N-(2-chloroacetyl)-N′-{3-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (115 mg, yield 85%). Next, N-(2-chloroacetyl)-N′-{3-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (50 mg) and potassium carbonate (28 mg) were added to chloroform, and indoline [starting compound C] (36 μl) was added to the mixture with stirring. The mixture was stirred at room temperature for 3 hr, and the reaction solution was filtered through Celite. The filtrate was then concentrated under the reduced pressure. The concentrate was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (33 mg, yield 56%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 10.64 (br, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.90 (d, J=2.7 Hz, 1H), 7.63 (s, 1H), 7.54-7.51 (m, 2H), 7.34 (s, 1H), 7.22-7.11 (m, 3H), 6.86-6.83 (m, 1H), 6.48 (d, J=7.8 Hz, 1H), 6.42 (d, J=5.6 Hz, 1H), 4.08 (s, 6H), 3.87 (s, 2H), 3.55-3.51 (m, 2H), 3.13-3.09 (m, 2H)

Mass spectrometric value (m/z): 533 [M+H]⁺

Example 9

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (415 mg) was dissolved in 10 ml of a 1% AcOH/DMF solution to prepare a solution. Further, aldehyde linker lanthanum (D-series; 28 μmol/unit) (10 units) was added to the solution. The reaction mixture was slowly shaken for 19 hr. Sodium boron triacetoxyhydride (475 mg) was added thereto, and the mixture was further slowly shaken for 24 hr. Lanthanum was taken out of the reaction solution and was washed with alternate N,N-dimethylformamide and dichloromethane each three times, followed by drying under the reduced pressure to give lanthanum with 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline supported thereon. This lanthanum (3 units) was added to 1 ml of dichloromethane, and a solution of N-(chlorocarbonyl)isocyanate [starting compound B] (55 μl) in dichloromethane (0.2 ml) was added to the mixture at 0° C. The mixture was slowly shaken overnight at room temperature. Further, a mixed solution composed of aniline [starting compound C] (68 μl), diisopropylamine (0.2 ml), and dichloromethane (0.3 ml) was then added thereto at 0° C. The mixture was shaken at room temperature for 7 hr and was then washed with alternate N,N-dimethylformamide and dichloromethane each five times. Drying under the reduced pressure was carried out, a 50% TFA/dichloromethane solution (1 ml) was added thereto, and the mixture was shaken at room temperature for 50 min to take off the product from lanthanum, followed by purification by thin layer chromatography on silica gel to give 6.8 mg of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 3.98 (s, 6H), 6.40 (d, J=5.4 Hz, 1H), 7.09 (m, 1H), 7.10 (d, J=9 Hz, 2H), 7.27 (t, J=7.8 Hz, 2H), 7.33 (s, 1H), 7.38 (d, J=7.8 Hz, 2H), 7.47 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 8.37 (d, J=5.4 Hz, 1H)

Mass spectrometric value (m/z): 457 [M−H]⁺

Example 10

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (500 mg) was dissolved in 20 ml of dichloromethane to prepare a solution, and N-(chlorocarbonyl)isocyanate [starting compound 13] (145 μl) was slowly added to the solution. The mixture was stirred at room temperature for 2.5 hr. 4-Fluoroaniline [starting compound C] (205 mg) and diisopropylamine (0.35 ml) were then added thereto at 0° C. Further, the temperature of the reaction solution was returned to room temperature before stirring for 2.5 hr. Water was added to the reaction solution, and the mixture was then extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The dried chloroform layer was concentrated under the reduced pressure, and the concentrate was then purified by chromatography on silica gel to give 380 mg of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 4.03 (s, 3H), 4.04 (s, 3H), 6.42 (d, J=5.4 Hz, 1H), 7.00 (m, 2H), 7.14 (d, J=9 Hz, 2H), 7.33 (br, 2H), 7.40 (s, 1H), 7.45 (br, 2H), 7.53 (s, 1H), 8.48 (d, J=5.4 Hz, 1H)

Mass spectrometric value (m/z): 475 [M−H]⁺

Example 11

N-{3-Fluoro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2-phenylacetylurea [starting compound A] (100 mg), potassium carbonate (150 mg), and 1,3-dibromopropane [starting compound C] (66 μl) were dissolved in dimethylformamide (5 ml) to prepare a solution which was then stirred at room temperature for 5 hr. Thereafter, morpholine [starting compound B] (57 μl) was further added thereto, and the mixture was stirred at room temperature for 3 hr. After the completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was then concentrated under the reduced pressure to give a crude. The crude was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give the title compound (23 mg, yield 18%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.07 (m, 2H), 2.44 (m, 4H), 2.53 (t, J=7.1 Hz, 2H), 3.66 (m, 4H), 3.69 (s, 2H), 3.96 (s, 3H), 4.20 (t, J=6.6 Hz, 2H), 6.33 (d, J=5.4 Hz, 1H), 7.11-7.45 (m, 8H), 7.49 (s, 1H), 7.61 (m, 1H), 8.01 (br, 1H), 8.41 (d, J=5.4 Hz, 1H), 10.59 (br, 1H)

Mass spectrometric value (m/z): 589 [M+H]⁺

Example 12

N-{3-Fluoro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2-phenylacetyl)urea [starting compound A] (100 mg), potassium carbonate (150 mg), and 1,4-dibromobutane [starting compound C] (78 μl) were dissolved in dimethylformamide (5 ml) to prepare a solution which was then stirred at room temperature for 5 hr. Thereafter, 1-methylpiperazine [starting compound B] (72 μl) was further added thereto, and the mixture was stirred at room temperature for 3 hr. After the completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was then concentrated under the reduced pressure to give a crude. The crude was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give the title compound (24 mg, yield 18%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.07 (br, 1H), 10.70 (br, 1H), 8.76 (d, J=6.3 Hz, 1H), 7.88 (d, J=11.7 Hz, 1H), 7.70 (s, 1H), 7.55 (s, 1H), 7.53-7.49 (m, 3H), 7.34-7.27 (m, 4H), 6.86 (br, 1H), 4.28-4.26 (m, 2H), 4.01 (s, 4H), 3.74 (s, 3H), 3.65-3.63 (m, 1H), 3.28-3.16 (m, 3H), 2.99-2.49 (m, 3H), 2.31-1.89 (m, 8H)

Mass spectrometric value (m/z): 616 [M+H]⁺

Example 13

N-{3-Fluoro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2-phenylacetylurea [starting compound A] (100 mg), potassium carbonate (150 mg), and 1,2-dibromoethane [starting compound C] (54 μl) were dissolved in dimethylformamide (5 ml) to prepare a solution which was then stirred at room temperature for 5 hr. Thereafter, piperidine [starting compound B] (64 μl) was further added thereto, and the mixture was stirred at room temperature for 3 hr. After the completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was then concentrated under the reduced pressure to give a crude. The crude was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give the title compound (22 mg, yield 18%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.08 (br, 1H), 10.71 (br, 1H), 8.77 (d, J=6.3 Hz, 1H), 7.88 (d, J=13.6 Hz, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 7.53-7.36 (m, 2H), 7.34-7.25 (m, 5H), 6.87 (d, J=6.3 Hz, 1H), 4.59-4.56 (m, 2H), 4.04 (s, 4H), 3.95-3.92 (m, 2H), 3.74 (s, 2H), 2.08 (s, 9H)

Mass spectrometric value (m/z): 573 [M+H]⁺

Example 14

N-{3-Fluoro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2-phenylacetyl)urea (100 mg), potassium carbonate (145 mg), and 1-bromo-3-chloropropane (53 μl) were dissolved in dimethylformamide (5 ml) to prepare a solution which was then stirred at room temperature for 5 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated under the reduced pressure to give a crude. The crude was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give the title compound (90 mg, yield 78%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.21 (br, 1H), 10.34 (br, 1H), 8.43 (d, J=5.4 Hz, 1H), 7.92 (d, J=10.2 Hz, 1H), 7.83 (d, J=12.2 Hz, 1H), 7.50 (s, 1H), 7.39-7.28 (m, 7H), 6.41 (d, J=5.1 Hz, 1H), 3.94 (s, 3H), 3.63 (s, 2H), 2.67 (m, 3H), 2.43 (s, 1H), 1.93-1.82 (m, 2H)

Mass spectrometric value (m/z): 538 [M+H]⁺

Example 15

Dimethyl methyl malonate [starting compound B] (1.33 ml) was dissolved in ethanol/water (10/1, 6 ml) to prepare a solution. Lithium hydroxide monohydrate (0.42 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under the reduced pressure to give 1.41 g of a crude. This crude (0.71 g), 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (1.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.97 g), and 1-hydroxybenzotriazole monohydrate (0.78 g) were dissolved in chloroform (30 ml), and the solution was heated under reflux overnight.

An aqueous saturated sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine. The chloroform layer was dried over anhydrous sodium sulfate, and the dried chloroform layer was concentrated under the reduced pressure to give a crude. The crude was dissolved in ethanol/water (10/1, 50 ml). Lithium hydroxide monohydrate (0.28 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under the reduced pressure. Water was added to the concentrate, and the solution was made weakly acidic by the addition of hydrochloric acid, followed by extraction with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the dried chloroform layer was concentrated under the reduced pressure to give 0.68 g of a crude (hereinafter referred to simply as “carboxylic acid”). This carboxylic acid (96 mg), 2,4-difluoroaniline [starting compound C] (0.037 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (70 mg), and 1-hydroxybenzotriazole monohydrate (56 mg) were dissolved in chloroform (4 ml), and the solution was heated under reflux overnight. The reaction solution was developed on diatomaceous earth impregnated with an aqueous saturated sodium hydrogencarbonate solution, followed by extraction with chloroform. The solvent in the extract was removed by evaporation to give a crude. The crude was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give 105 mg of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 1.74 (d, J=7.3 Hz, 3H), 3.47 (q, J=7.3 Hz, 1H), 4.05 (s, 3H), 4.06 (s, 3H), 6.47 (d, J=5.4 Hz, 1H), 6.87-6.95 (m, 2H), 7.18 (d, J=9.0 Hz, 2H), 7.48 (s, 1H), 7.55 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 8.15-8.23 (m, 1H), 8.45-8.50 (m, 2H), 8.63 (br, 1H)

Mass spectrometric value (m/z): 508 [M+H]⁺

Example 268

Phenylacetyl chloride (86 μl) and potassium thiocyanate (80 mg) were dissolved in acetonitrile (50 ml) to prepare a solution which was then stirred at 40° C. for 50 min. Acetonitrile was removed by evaporation under the reduced pressure to give a crude. An aqueous saturated sodium hydrogencarbonate solution and ethyl acetate were added to the crude, and the mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure to give a crude which was then dissolved in toluene/ethanol (1/1). 3-Fluoro-4-{[7-(3-morpholinopropoxy)-6-methoxy-4-quinolyl]oxy}aniline (70 mg) was added to the solution, and the mixture was stirred at room temperature for 3 hr. The reaction solvent was removed by evaporation under the reduced pressure, and the residue was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give the title compound (43.6 mg, yield 44.0%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.13 (m, 2H), 2.49 (m, 4H), 2.58 (t, J=7.2 Hz, 2H), 3.73 (m, 4H), 3.76 (s, 2H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.44 (d, J=5.1 Hz, 1H), 7.22-7.48 (m, 8H), 7.54 (s, 1H), 7.93 (m, 1H), 8.46 (br, 1H), 8.50 (d, J=5.1 Hz, 1H), 12.47 (br, 1H)

Mass spectrometric value (m/z): 605 [M+H]⁺

Example 269

3-Fluoro-4-{[7-(3-morpholinopropoxy)-6-methoxy-4-quinolyl]oxy}aniline (60 mg) was dissolved in chloroform (15 ml) to prepare a solution. 3-(4-Fluoroanilino)-3-oxopropanoic acid (50 mg), 1-hydroxybenzotriazole monohydrate (43 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg) were added to the solution, and the mixture was heated under reflux for 3 hr, followed by washing with an aqueous saturated sodium hydrogencarbonate solution. The solvent was then removed by evaporation under the reduced pressure to give a crude. The crude was purified by column chromatography on silica gel using chloroform/methanol for development to give the title compound (41 mg, yield 48%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.04-2.10 (m, 2H), 2.35-2.46 (m, 4H), 2.51 (t, J=7.1 Hz, 2H), 3.50 (s, 2H), 3.63-3.68 (m, 4H), 3.96 (s, 3H), 4.18 (t, J=6.6 Hz, 2H), 6.32 (d, J=5.3 Hz, 1H), 6.97-7.02 (m, 2H), 7.13-7.24 (m, 2H), 7.36 (s, 1H), 7.43-7.50 (m, 2H), 7.49 (s, 1H), 7.70-7.74 (m, 1H), 8.40 (d, J=5.3 Hz, 1H), 8.55 (s, 1H), 9.35 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 607 [M+H]⁺

Compounds of Examples 1 to 15, 268, and 269 had the following respective structures.

Compounds of Examples 16 to 267 were synthesized as described in Examples 1 to 15, 268, and 269. For these compounds, chemical structural formulae, starting compounds, synthesis methods, and data for identifying the compounds are as follows.

Ex. Starting No. Compound structure compound A  16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

Ex. No. Starting compound B Starting compound C Mass spectrometric value (m/z) H¹-MNR Synthesis method^(a)  16

476 [M + H]+ (CDCl3, 400 MHz): δ 3.75 (s, 2H), 4.01 (s, 3H), 4.02 (s, 3H), 6.49 (d, J = 5.3 Hz, 1)H, 6.95-7.00 (m, 2H), 7.28-7.48 (m, 5H), 7.41 (s, 1H), 7.50 (s, 1H), 8.01 (s, 1H), 8.18 (t, J = 9.1 Hz, 1H), 8.49 (d, J = 5.3 Hz, 1H), 10.74 (s, 1H) Ex. 4    17

476 [M + H]+ (CDCl3, 400 MHz): δ 3.75 (s, 2H), 4.03 (s, 3H), 4.04 (s, 3H), 6.38 (d, J = 5.3 Hz, 1H), 6.97-7.42 (m, 7H), 7.40 (s, 1H), 7.55 (s, 1H), 7.65-7.68 (m, 1H), 8.09 (s, 1H), 8.46 (d, J = 5.3 Hz, 1H), 10.60 (s, 1H) Ex. 4    18

492 [M + H]+ (CDCl3, 400 MHz): δ 3.75 (s, 2H), 4.03 (s, 3H), 4.04 (s, 3H), 6.29 (d, J = 5.3 Hz, 1H), 7.17-7.43 (m, 7H), 7.41 (s, 1H), 7.56 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 8.07 (br, 1H), 8.45 (d, J = 5.3 Hz, 1H), 10.62 (s, 1H) Ex. 4    19

482 [M + H]+ (DMSO-d6, 400 MHz): δ 11.23 (br, 1H), 10.75 (br, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.22 (m, 1H), 7.52-7.37 (m, 3H), 7.23 (m, 1H), 7.10-7.02 (m, 2H), 6.87- 6.85 (m, 1H), 6.56 (d, J = 5.4 Hz, 1H), 3.94 (s, 6H), 3.77 (s, 2H) Ex. 3    20

482 [M + H]+ (DMSO-d6, 400 MHz): δ 11.00 (br, 1H), 10.63 (br, 1H), 8.48 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 14.15 Hz, 1H), 7.52- 7.38 (m, 5H), 7.23 (m, 1H), 7.02 (d, J = 6.1 Hz, 1H), 6.45 (d, J = 5.4 Hz, 1H), 3.95 (s, 6H), 3.77 (s, 2H) Ex. 3    21

498 [M + H]+ (DMSO-d6, 400 MHz): δ 10.63 (br, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.01 (s, 1H), 7.59-7.38 (m, 5H), 7.23 (s, 1H), 7.09 (d, J = 4.8 Hz, 1H), 7.02 (d, J = 4.8 Hz, 1H), 6.35 (d, J = 5.4 Hz, 1H), 3.94 (s, 6H), 3.77 (s, 2H) Ex. 3    22

476 [M + H]+ (DMSO-d6, 400 MHz): δ 10.96 (br, 1H), 10.50 (br, 1H), 8.31 (d, J = 5.4 Hz, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.38- 7.08 (m, 8H), 6.45 (d, J = 5.1 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.74 (s, 2H) Ex. 3    23

494 [M + H]+ (DMSO-d6, 400 MHz): δ 11.03 (br, 1H), 10.61 (br, 1H), 8.47 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 14.1 Hz, 1H), 7.52 (s, 1H), 7.42-7.08 (m, 6H), 6.85 (br, 1H), 6.44 (d, J = 4.9 Hz, 1H), 3.94 (s, 6H), 3.75 (s, 2H) Ex. 3    24

510 [M + H]+ (DMSO-d6, 400 MHz): δ 11.08 (br, 1H), 10.62 (br, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.59- 7.57 (m, 1H), 7.52 (br, 1H), 7.42-7.09 (m, 5H), 6.87 (br, 1H), 6.34 (d, J = 5.1 Hz, 1H), 3.93 (s, 6H), 3.75 (s, 2H) Ex. 3    25

498 [M + Na]+ (CDCl3, 400 MHz): δ 3.79 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.47 (d, J = 5.1 Hz, 1H), 7.13-7.42 (m, 6H), 7.46 (s, 1H), 7.55 (s, 1H), 7.60 (d, J = 9.0 Hz, 2H), 7.73 (s, 1H), 8.48 (d, J = 5.4 Hz, 1H), 10.47 (s, 1H) Ex. 3    26

516 [M + Na]+ (CDCl3, 400 MHz): δ 3.80 (s, 2H), 4.04 (s, 3H), 4.06 (s, 3H), 6.52 (d, J = 5.4 Hz, 1H), 6.96-7.02 (m, 2H), 7.13-7.42 (m, 4H), 7.46 (s, 1H), 7.49 (s, 1H), 7.76 (s, 1H), 8.20-8.26 (m, 1H), 8.51 (d, J = 5.4 Hz, 1H), 10.68 (s, 1H) Ex. 3    27

494 [M + H]+ (DMSO-d6, 400 MHz): δ 10.62 (br, 1H), 8.48 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 13.9 Hz, 1H), 7.52-7.11 (m, 8H), 6.93 (br, 1H), 6.45 (d, J = 5.1 Hz, 1H), 3.85 (s, 2H), 3.44 (s, 6H) Ex. 3    28

532 [M + Na]+ (CDCl3, 400 MHz): δ 3.79 (s, 2H), 4.06 (s, 3H), 4.07 (s, 3H), 6.34 (d, J = 5.4 Hz, 1H), 7.14-7.54 (m, 7H), 7.59 (s, 1H), 7.70 (s, 1H), 7.84 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 5.4 Hz, 1H), 10.55 (s, 1H) Ex. 3    29

464 [M + H]+ (DMSO-d6, 400 MHz): δ 10.97 (br, 1H), 10.47 (br, 1H), 8.47 (d, J = 5.4 Hz, 1H), 7.67-7.65 (m, 2H), 7.50 (s, 1H), 7.44 (d,J = 6.6 Hz, 1H), 7.39 (s, 1H), 7.25-7.23 (m, 2H), 7.01-6.99 (m, 2H), 6.46 (d, J = 5.4 Hz, 1H), 4.00 (s, 2H), 3.98 (s, 6H) Ex. 3    30

482 [M + H]+ (DMSO-d6, 400 MHz): δ 11.17 (br, 1H), 10.69 (br, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.23-8.19 (m, 1H), 7.47-7.33 (m, 3H), 7.14 (d, J = 8.8 Hz, 1H), 7.02- 6.89 (m, 3H), 6.55 (d, J = 5.1 Hz, 1H), 3.98 (s, 2H), 3.92 (s, 6H) Ex. 3    31

482 [M + H]+ (DMSO-d6, 400 MHz): δ 8.48 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 13.4 Hz, 1H), 7.53-7.33 (m, 4H), 7.01-6.89 (m, 5H), 6.45 (d, J = 5.1 Hz, 1H), 3.97 (s, 2H), 3.95 (s, 6H) Ex. 3    32

498 [M + H]+ (DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.54 (br, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.00 (s, 1H), 7.61-7.59 (m, 1H), 7.53 (s, 1H), 7.45-7.33 (m, 3H), 7.01- 6.89 (m, 2H), 6.35 (d, J = 5.1 Hz, 1H), 3.99 (s, 2H), 3.94 (s, 6H) Ex. 3    33

512 [M + H]+ (CDCl3, 400 MHz): δ 3.74 (s, 2H), 4.01 (s, 3H), 4.03 (s, 3H), 6.49 (d, J = 5.3 Hz, 1H), 6.86-6.99 (m, 4H), 7.21-7.32 (m, 1H), 7.41 (s, 1H), 7.47 (s, 1H), 8.15 (br, 1H), 8.20 (t, J = 9.5 Hz, 1H), 8.49 (d, J = 5.3 Hz,1H), 10.63 (s, 1H) Ex. 3    34

512 [M + H]+ (CDCl3, 400 MHz): δ 3.74 (s, 2H), 4.02 (s, 3H), 4.04 (s, 3H), 6.39 (d, J = 5.3 Hz, 1H), 6.88-7.69 (m, 6H), 7.24 (s, 1H), 7.55 (s, 1H), 8.29 (br, 1H), 8.48 (d, J = 5.3 Hz, 1H), 10.56 (s, 1H) Ex. 3    35

512 [M + H]+ (CDCl3, 400 MHz): δ 3.73 (s, 2H), 4.06 (s, 6H), 6.42 (d, J = 5.1 Hz, 1H), 7.03-7.08 (m, 1H), 7.14-7.26 (m, 4H), 7.49 (br, 1H), 7.58 (s, 1H), 7.67-7.72 (m, 1H), 8.13 (br, 1H), 8.51 (d, J = 5.1 Hz, 1H), 10.56 (s, 1H) Ex. 3    36

494 [M + H]+ (CDCl3, 400 MHz): δ 3.74 (s, 2H), 4.01 (s, 3H), 4.03 (s, 3H), 6.50 (d, J = 5.3 Hz, 1H), 6.51-7.10 (m, 5H), 7.31-7.35 (m, 1H), 7.42 (s, 1H), 7.47 (s, 1H), 8.18 (t, J = 9.5 Hz, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.89 (s, 1H), 10.74 (s, 1H) Ex. 3    37

494 [M + H]+ (CDCl3, 400 MHz): δ 3.74 (s, 2H), 4.03 (s, 3H), 4.04 (s, 3H), 6.39 (d, J = 5.3 Hz, 1H), 7.02-7.68 (m, 7H), 7.41 (s, 1H), 7.55 (s, 1H), 8.26 (s, 1H), 8.47 (d, J = 5.3 Hz, 1H), 10.60 (s, 1H) Ex. 3    38

506 [M + H]+ (DMSO-d6, 400 MHz): δ 10.98 (br, 1H), 10.84 (br, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.38-7.04 (m, 6H), 6.84-6.82 (m, 1H), 6.49 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.72 (s, 2H) Ex. 3    39

516 [M + Na]+ (CDCl3, 400 MHz): δ 3.72 (s, 2H), 4.04 (s, 3H), 4.05 (s, 3H), 6.47 (d, J = 5.4 Hz, 1H), 7.03-7.09 (m, 1H), 7.15-7.23 (m, 4H), 7.44 (s, 1H), 7.54 (s, 1H), 7.60 (d, J = 9.0 Hz, 2H), 8.49 (d, J = 5.4 Hz, 1H), 8.67 (s, 1H), 10.51 (s, 1H) Ex. 3    40

570 [M + H]+ (DMSO-d6, 400 MHz): δ 11.16 (br, 1H), 10.75 (br, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.24-8.19 (m, 1H), 7.53-7.35 (m, 10H), 7.19-7.11 (m, 3H), 6.56 (d, J = 5.4 Hz, 1H), 5.31 (s, 2H), 3.94 (s, 3H), 3.75 (s, 2H) Ex. 3^(b)   41

621 [M + H]+ (DMSO-d6, 400 MHz): δ 11.03 (br, 1H), 10.60 (br, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.80 (d, J = 13.6 Hz, 1H), 7.51- 7.07 (m, 5H), 6.85 (br, 3H), 6.43 (d, J = 5.1 Hz, 1H), 4.18-4.16 (m, 2H), 3.95 (s, 3H), 3.58-3.56 (m, 3H), 2.89 (s, 2H), 2.73 (s, 2H), 2.36 (s, 5H), 1.84 (m, 2H), 1.63 (m, 2H) Ex. 12   42

619 [M + H]+ (DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.62 (br, 1H), 8.46 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 13.4 Hz, 1H), 7.53 (s, 1H), 7.41-7.33 (m, 5H), 7.19-7.14 (m, 2H), 6.44 (d, J = 5.1 Hz, 1H), 4.19 (m, 2H), 3.95 (s, 2H), 3.75 (s, 2H), 3.29-3.27 (m, 3H), 2.50-2.49 (m, 2H), 1.90-1.85 (m, 3H), 1.69 (m, 9H) Ex. 12   43

634 [M + H]+ (DMSO-d6, 400 MHz): δ 11.03 (br, 1H), 10.61 (br, 1H), 8.45 (d, J = 3.9 Hz, 1H), 7.81 (d, J = 13.4 Hz, 1H), 7.50 (s, 1H), 7.41-7.34 (m, 5H), 7.18-7.14 (m, 2H), 6.42 (d, J = 8.1 Hz, 1H), 4.18-4.15 (m, 2H), 3.94 (s, 3H), 3.74 (s, 2H), 3.29-3.28 (m, 4H), 2.50-2.49 (m, 4H), 2.36 (br, 2H), 2.18-2.17 (m, 3H), 1.83 (m, 2H), 1.61 (m, 2H) Ex. 12   44

621 [M + H]+ (DMSO-d6, 400 MHz): δ 11.16 (br, 1H), 10.75 (br, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.22 (m, 1H), 7.95 (s, 1H), 7.46- 7.08 (m, 3H), 6.86 (br, 4H), 6.55 (d, J = 5.4 Hz, 1H), 4.19-4.17 (m, 2H), 3.92 (s, 4H), 3.75 (s, 2H), 3.57 (br, 4H), 2.49 (br, 5H), 1.84 (m, 2H), 1.62 (m, 2H) Ex. 12   45

619 [M + H]+ (DMSO-d6, 400 MHz): δ 11.16 (br, 1H), 10.76 (br, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.25-8.20 (m, 1H), 7.48 (s, 1H), 7.42-7.34 (m, 4H), 7.19-7.10 (m, 3H), 6.56 (d, J = 5.4 Hz, 1H), 4.19 (br, 2H), 3.93 (s, 3H), 3.75 (s, 2H), 3.34- 3.28 (m, 6H), 2.50-2.49 (m, 5H), 1.91- 1.85 (m, 5H) Ex. 12   46

607 [M + H]+ (DMSO-d6, 400 MHz): δ 11.21 (br, 1H), 10.54 (br, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.81 (d, J = 13.5 Hz, 1H), 7.48- 7.06 (m, 5H), 6.51 (br, 3H), 6.31 (d, J = 5.1 Hz, 1H), 4.18-4.13 (m, 2H), 3.94 (s, 3H), 3.57-3.50 (m, 3H), 2.89 (s, 2H), 2.73 (s, 2H), 2.36 (br, 3H), 1.81 (m, 2H), 1.61 (m, 2H) Ex. 11   47

605 [M + H]+ (DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.62 (br, 1H), 8.48 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 13.2 Hz, 1H), 7.55 (s, 1H), 7.45-7.35 (m, 5H), 7.19-7.15 (m, 2H), 6.46 (d, J = 5.4 Hz, 1H), 4.18 (br, 2H), 3.96 (s, 3H), 3.75 (s, 3H), 3.51 (br, 1H), 3.29 (m, 5H), 2.50-2.49 (m, 4H), 2.26 (m, 2H), 1.83 (m, 1H), 1.70 (m, 1H) Ex. 11   48

591 [M + H]+ (DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.62 (br, 1H), 8.48 (d, J = 5.1 Hz, 1H), 7.81 (d, J = 14.2 Hz, 1H), 7.55 (s, 1H), 7.48-7.34 (m, 5H), 7.18-7.14 (m, 2H), 6.45 (d, J = 4.9 Hz, 1H), 3.96 (s, 3H), 3.75 (s, 2H), 2.50-2.49 (m, 7H), 1.91-1.23 (m, 7H) Ex. 13   49

606 [M + H]+ (DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.61 (br, 1H), 8.46 (d, J = 5.4 Hz, 1H), 7.80 (d, J = 13.6 Hz, 1H), 7.52 (s, 1H), 7.43-7.35 (m, 5H), 7.18-7.14 (m, 2H), 6.43 (d, J = 5.1 Hz, 1H), 4.27 (br, 2H), 3.94 (s, 3H), 3.74 (s, 2H), 2.89-2.38 (m, 8H), 1.27-1.39 (m, 5H) Ex. 13   50

605 [M + H]+ (DMSO-d6, 400 MHz): δ 11.16 (br, 1H), 10.77 (br, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.23 (m, 1H), 7.50-7.17 (m, 8H), 6.95 (d, J = 5.3 Hz, 1H), 4.26 (br, 2H), 3.93 (s, 4H), 3.75 (br, 2H), 3.50 (m, 1H), 3.29 (m, 3H), 2.94 (m, 1H), 2.67 (s, 1H), 2.49 (m, 3H), 2.32-2.25 (m, 2H), 1.83 (m, 1H), 1.69 (m, 1H) Ex. 11   51

620 [M + H]+ (DMSO-d6, 400 MHz): δ 11.10 (br, 1H), 10.76 (br, 1H), 8.50 (d, J = 5.1 Hz, 1H), 8.23 (m, 1H), 7.50-7.14 (m, 8H), 6.93 (d, J = 5.1 Hz, 1H), 4.22 (br, 2H), 3.94 (s, 3H), 3.75 (s, 2H), 3.29 (m, 6H), 2.67 (s, 1H), 2.52-2.49 (m, 7H), 2.32 (s, 1H) Ex. 11   52

587 [M + H]+ (DMSO-d6, 400 MHz): δ 11.05 (br, 1H), 10.63 (br, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.81 (d, J = 13.9 Hz, 1H), 7.53 (s, 3H), 7.43-7.27 (m, 8H), 6.44 (d, J = 5.1 Hz, 1H), 4.23 (m, 1H), 3.95 (s, 1H), 3.74 (s, 2H), 3.28-3.26 (m, 4H), 2.89 (s, 1H), 2.73 (s, 1H), 2.50-2.48 (m, 5H), 1.67-1.23 (m, 4H) Ex. 11   53

602 [M + H]+ (DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.63 (br, 1H), 8.45 (d, J = 5.4 Hz, 1H), 7.95 (d, J = 11.2 Hz, 1H), 7.80 (d, J = 13.9 Hz, 1H), 7.50 (s, 1H), 7.39-7.28 (m, 5H), 6.41 (d, J = 5.1 Hz, 1H), 4.19-4.16 (m, 2H), 3.94 (s, 3H), 3.74 (s, 2H), 3.36-3.27 (m, 7H), 2.89 (s, 1H), 2.73 (s, 1H), 2.32-2.19 (m, 6H), 1.98-1.95 (m, 2H) Ex. 11   54

575 [M + H]+ (DMSO-d6, 400 MHz): δ 11.12 (br, 1H), 10.51 (br, 1H), 8.45 (d, J = 5.3 Hz, 1H), 7.80 (d, J = 13.9 Hz, 1H), 7.52 (s, 1H), 7.43-7.28 (m, 8H), 6.41 (d, J = 5.3 Hz, 1H), 4.29 (br, 2H), 3.94 (s, 3H), 3.89 (s, 2H), 3.61-3.56 (m, 4H), 2.52-2.49 (m, 6H) Ex. 13   55

593 [M + H]+ (DMSO-d6, 400 MHz): δ 11.10 (br, 1H), 10.75 (br, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.21 (m, 1H), 7.53-7.09 (m, 8H), 6.44 (d, J = 5.3 Hz, 1H), 4.28 (br, 2H), 3.94 (s, 3H), 3.88 (s, 2H), 3.60- 3.51 (m, 4H), 3.25-3.24 (m, 2H), 2.51- 2.48 (m, 4H) Ex. 13   56

510 [M + H]+ (DMSO-d6, 400 MHz): δ 12.69 (br, 1H), 12.04 (br, 1H), 8.72 (d, J = 5.9 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 7.1 Hz, 1H), 7.68-7.61 (m, 4H), 7.48-7.43 (m, 4H), 6.79 (d, J = 5.9 Hz, 1H), 4.00 (s, 6H) Ex. 2    57

528 [M + H]+ (DMSO-d6, 400 MHz): δ 12.54 (br, 1H), 12.21 (br, 1H), 8.57 (d, J = 5.4 Hz, 1H), 8.23-8.14 (m, 3H), 8.05 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 6.1 Hz, 1H), 7.69-7.52 (m, 3H), 7.48-7.41 (m, 3H), 7.19 (m, 1H), 6.69 (d, J = 5.1 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H) Ex. 2    58

492 [M + H]+ (DMSO-d6, 400 MHz): δ 12.26 (br, 1H), 11.89 (br, 1H), 8.55 (d, J = 5.1 Hz, 1H), 8.05 (t, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.29-7.36 (m, 6H), 7.13 (d, J = 9.5 Hz, 1H), 6.64 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.83 (s, 2H) Ex. 1    59

508 [M + H]+ (DMSO-d6, 400 MHz): δ 3.92 (s, 3H), 3.95 (s, 3H), 4.04 (s, 2H), 6.54 (d, J = 5.1 Hz, 1H), 7.27-7.50 (m, 7H), 7.74- 7.79 (m, 2H), 8.31 (s, 1H), 8.51 (d, J = 5.1 Hz, 1H), 11.80-11.83 (br, 1H) Ex. 2    60

474 [M + H]+ (DMSO-d6, 400 MHz): δ 12.47 (br, 1H), 11.81 (br, 1H), 8.14-8.16 (m, 1H), 7.69 (m, 1H), 7.51 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.25-7.35 (m, 7H), 6.51 (d, J = 6.1 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.82 (s, 2H) Ex. 1    61

480 [M + H]+ (DMSO-d6, 400 MHz): δ 12.41 (br, 1H), 11.48 (br, 1H), 8.63 (m, 1H), 7.81-7.84 (m, 2H), 7.59 (s, 1H), 7.44 (s, 1H), 7.34-7.36 (m, 2H), 6.67 (m, 1H), 3.95 (s, 6H), 2.37 (d, J = 6.8 Hz, 2H), 1.69 (m, 3H), 1.19-1.25 (m, 6H), 0.86-1.00 (m, 2H) Ex. 2    62

456 [M + H]+ (DMSO-d6, 400 MHz): δ 12.48 (br, 1H), 10.09 (br, 1H), 8.54 (d, J = 6.3 Hz, 1H), 8.09 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.26-7.25 (m, 3H), 6.74 (d, J = 6.1 Hz, 1H), 4.22 (s, 3H), 4.16 (s, 3H), 3.79-3.77 (m, 2H), 3.66- 3.62 (m, 2H), 2.65-2.64 (m, 2H), 1.23- 1.18 (m, 3H) Ex. 2    63

508 [M + H]+ (CDCl3, 400 MHz): δ 3.76 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.39 (d, J = 5.1 Hz, 1H), 7.23-7.47 (m, 6H), 7.51 (s, 1H), 7.57 (s, 1H), 7.61-7.64 (m, 1H), 8.00 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 5.4 Hz, 1H) Ex. 1    64

520 [M + H]+ (DMSO-d6, 400 MHz): δ 12.62 (br, 1H), 11.64 (br, 1H), 8.51 (d, J = 5.4 Hz, 1H), 8.64 (d, J = 11.5 Hz, 1H), 7.57- 7.42 (m, 4H), 7.16-7.13 (m, 4H), 6.51 (d, J = 5.4 Hz, 1H), 3.96 (s, 8H), 2.91-2.88 (m, 1H), 2.79-7.75 (m, 1H), 2.31 (s, 3H) Ex. 2    65

508 [M + H]+ (DMSO-d6, 400 MHz): δ 12.37 (br, 1H), 11.89 (br, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.37-7.23 (m, 6H), 6.63 (d, J = 5.1 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.84 (s, 2H) Ex. 1    66

480 [M + H]+ (DMSO-d6, 400 MHz): δ 12.4 (br, 1H), 11.69 (br, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.49-7.00 (m, 9H), 6.56 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.84 (s, 2H) Ex. 2    67

488 [M + H]+ (DMSO-d6, 400 MHz): δ 12.42 (br, 1H), 11.73 (br, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.30 (s, 1H), 7.66-7.63 (m, 2H), 7.55 (s, 1H), 7.39 (s, 1H), 7.35-7.19 (m, 8H), 6.34 (d, J = 5.4 Hz, 1H), 3.94 (s, 6H), 3.82 (s, 2H) Ex. 1    68

504 [M + H]+ (DMSO-d6, 400 MHz): δ 11.76 (br, 1H), 10.95 (br, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.30 (s, 1H), 7.63 (s, 2H), 7.51 (s, 1H), 7.38-7.22 (m, 6H), 6.31 (d, J = 5.4 Hz, 1H), 3.94 (s, 3H), 3.82 (s, 6H), 3.69 (s, 2H) Ex. 1    69

504 [M + H]+ (DMSO-d6, 400 MHz): δ 12.71 (br, 1H), 11.71 (br, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 7.38-7.11 (m, 5H), 7.03 (s, 1H), 6.87 (d, J = 11.5 Hz, 1H), 6.57 (d, J = 5.1 Hz, 1H), 3.95 (s, 9H), 3.83 (s, 2H) Ex. 1    70

543 [M + H]+ (DMSO-d6, 400 MHz): δ 12.43 (br, 1H), 11.89 (br, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.07 (s, 2H), 7.55 (s, 1H), 7.42 (s, 1H), 7.35-7.28 (m, 5H), 6.33 (d, J = 5.3 Hz, 1H), 3.95 (s, 6H), 3.83 (s, 2H) Ex. 1    71

492 [M + H]+ (DMSO-d6, 400 MHz): δ 12.39 (br, 1H), 11.73 (br, 1H), 8.53 (d, J = 5.4 Hz, 1H), 7.75 (d, J = 9.0 Hz, 2H), 7.51 (s, 1H), 7.41-7.16 (m, 7H), 6.56 (d, J = 5.4 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.83 (s, 2H) Ex. 2    72

510 [M + H]+ (DMSO-d6, 400 MHz): δ 12.22 (br, 1H), 11.89 (br, 1H), 8.58 (d, J = 5.4 Hz, 1H), 8.04 (t, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.43-7.11 (m, 7H), 6.68 (d, J = 5.4 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.57 (s, 2H) Ex. 2    73

527 [M + H]+ (DMSO-d6, 400 MHz): δ 12.43 (br, 1H), 11.83 (br, 1H), 8.61 (d,J = 5.6 Hz, 1H), 8.15 (s, 1H), 7.73-7.70 (m, 1H), 7.60 (s, 1H), 7.53-7.10 (m, 6H), 6.55 (d, J = 5.1 Hz, 1H), 3.97 (s, 6H), 3.84 (s, 2H) Ex. 2    74

510 [M + H]+ (DMSO-d6, 400 MHz): δ 3.88 (s, 2H), 3.91 (s, 3H), 3.95 (s, 3H), 6.64 (d, J = 5.1 Hz, 1H), 7.12-7.22 (m, 4H), 7.35-7.37 (m, 4H), 7.99-8.04 (m, 1H), 8.55 (d, J = 5.3 Hz, 1H), 11.90 (s, 1H), 12.18 (s, 1H) Ex. 2    75

510 [M + H]+ (DMSO-d6, 400 MHz): δ 3.87 (s, 2H), 3.94 (s, 3H), 3.95 (s, 3H), 6.49 (d, J = 4.9 Hz, 1H), 7.08-7.23 (m, 3H), 7.34- 7.56 (m, 5H), 8.00-8.03 (m, 1H), 8.50 (d, J = 5.1 Hz, 1H), 11.82 (s, 1H), 12.44 (s, 1H) Ex. 2    76

526 [M + H]+ (DMSO-d6, 400 MHz): δ 3.87 (s, 2H), 3.93 (s, 3H), 3.95 (s, 3H), 6.40 (d, J = 5.4 Hz, 1H), 7.09-7.24 (m, 3H), 7.35- 7.54 (m, 4H), 7.65-7.71 (m, 1H), 8.09- 8.13 (m, 1 Hz, 1H), 8.50 (d, J = 5.4 Hz, 1H), 11.82 (s, 1H), 12.38 (s, 1H) Ex. 2    77

488 [M + H]+ (DMSO-d6, 400 MHz): δ 2.31 (s, 3H), 3.78 (s, 2H), 3.93 (s, 3H), 3.95 (s, 3H), 6.39 (d, J = 5.1 Hz, 1H), 7.05- 7.27 (m, 5H), 7.41 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.67 (dd, J = 2,4 8.5 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 11.79 (s, 1H), 12.44 (s, 1H) Ex. 2    78

522 [M + H]+ (DMSO-d6, 400 MHz): δ 2.30 (s, 3H), 3.77 (s, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 6.53 (d, J = 5.1 Hz, 1H), 7.08- 7.31 (m, 5H), 7.40 (s, 1H), 7.48 (s, 1H), 7.74 (d, J = 8.7 Hz, 2H), 8.49 (d, J = 5.1 Hz, 1H), 11.71 (s, 1H), 12.42 (s, 1H) Ex. 2    79

488 [M + H]+ (DMSO-d6, 400 MHz): δ 2.29 (s, 3H), 3.89 (s, 2H), 4.02 (s, 3H), 4.04 (s, 3H), 6.87 (d, J = 6.6 Hz, 1H), 7.12- 7.30 (m, 4H), 7.44 (d, J = 9.0 Hz, 2H), 7.51 (s, 1H), 7.74 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 8.12 (d, J = 6.4 Hz, 1H), 11.77 (s, 1H), 12.49 (s, 1H) Ex. 2    80

510 [M + H]+ (DMSO-d6, 400 MHz): δ 12.45 (br, 1H), 11.87 (br, 1H), 8.56 (d, J = 5.6 Hz, 1H), 8.05-8.02 (m, 1H), 7.56-7.18 (m, 8H), 6.57 (d, J = 5.4 Hz, 1H), 3.96 (s, 8H) Ex. 2    81

510 [M + H]+ (DMSO-d6, 400 MHz): δ 12.19 (br, 1H), 11.95 (br, 1H), 8.62 (d, J = 5.6 Hz, 1H), 8.07-8.05 (m, 1H), 7.51 (s, 1H), 7.43-7.18 (m, 7H), 6.72 (d, J = 5.4 Hz, 1H), 3.97 (s, 8H) Ex. 2    82

522 [M + H]+ (DMSO-d6, 400 MHz): δ 2.29 (s, 3H), 3.77 (s, 2H), 3.93 (s, 3H), 3.95 (s, 3H), 6.39 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.41 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.66 (dd, J = 2.7, 9.0 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 11.78 (s, 1H), 12.44 (s, 1H) Ex. 2    83

522 [M + H]+ (DMSO-d6, 400 MHz): δ 3.79 (s, 3H), 3.81 (s, 2H), 3.94 (s, 3H), 3.95 (s, 3H), 6.49 (d, J = 5.1 Hz, 1H), 6.88- 7.03 (m, 2H), 7.20-7.32 (m, 2H), 7.41 (s, 1H), 7.44-7.58 (m, 3H), 8.05 (d, J = 12.4 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 11.71 (s, 1H), 12.55 (s, 1H) Ex. 2    84

506 [M + H]+ (CDCl3, 400 MHz): δ 2.36 (s, 3H), 3.77 (s, 2H), 4.05 (s, 6H), 6.46 (d, J = 5.1 Hz, 1H), 7.22-7.34 (m, 5H), 7.41 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.55 (s, 1H), 7.95 (dd, J = 2.4, 11.7 Hz, 1H), 8.37 (s, 1H), 8.51 (d, J = 5.4 Hz, 1H), 12.50 (s, 1H) Ex. 2    85

498 [M + H]+ (DMSO-d6, 400 MHz): δ 12.50 (br, 1H), 11.78 (br, 1H), 8.56 (d, J = 5.1 Hz, 1H), 7.56-7.28 (m, 3H), 7.11-7.00 (m, 5H), 6.57 (m, 1H), 3.95 (s, 6H), 3.84 (s, 2H) Ex. 2    86

510 [M + H]+ (DMSO-d6, 400 MHz): δ 12.71 (br, 1H), 11.67 (br, 1H), 8.64 (d, J = 5.1 Hz, 1H), 8.52-8.48 (m, 1H), 7.52-7.40 (m, 4H), 7.12-7.04 (m, 3H), 6.59 (d, J = 5.1 Hz, 1H), 3.95 (s, 6H), 3.85 (s, 5H) Ex. 2    87

527 [M + H]+ (DMSO-d6, 400 MHz): δ 12.45 (br, 1H), 11.91 (br, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.05-8.03 (m, 1H), 7.54-7.33 (m, 8H), 6.56-6.54 (m, 1H), 4.04 (s, 2H), 3.95 (s, 6H) Ex. 2    88

492 [M + H]+ (DMSO-d6, 400 MHz): δ 12.57 (br, 1H), 11.45 (br, 1H), 8.52 (d, J = 5.1 Hz, 1H), 7.79-7.76 (m, 2H), 7.57 (s, 1H), 7.45 (s, 1H), 7.31-7.28 (m, 2H), 6.54 (d, J = 5.1 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.31 (s, 2H), 2.49-2.30 (m, 2H), 1.52-1.08 (m, 9H) Ex. 2    89

510 [M + H]+ (DMSO-d6, 400 MHz): δ 12.41 (br,1H), 11.93 (br, 1H), 8.56 (d, J = 5.1 Hz, 1H), 8.15-8.07 (m, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 7.34 (d, J = 13.6 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 5.1 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.31 (s, 2H), 2.45-2.31 (m, 2H), 1.51-1.07 (m, 9H) Ex. 2    90

510 [M + H]+ (DMSO-d6, 400 MHz): δ 12.66 (br, 1H), 11.54 (br, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.08 (m, 1H), 7.55-7.43 (m, 4H), 6.54 (d, J = 5.6 Hz, 1H), 3.96 (s, 6H), 3.31 (s, 2H), 2.43-2.30 (m, 2H), 1.48- 1.06 (m, 9H) Ex. 2    91

527 [M + H]+ (DMSO-d6, 400 MHz): δ 12.59 (br, 1H), 11.54 (br, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.17-8.15 (m, 1H), 7.70-7.68 (m, 1H), 7.53 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 6.42 (d, J = 5.1 Hz, 1H), 3.94 (s, 6H), 3.31 (s, 2H), 2.42- 2.31 (m, 2H), 1.47-1.05 (m, 9H) Ex. 2    92

506 [M + H]+ (DMSO-d6, 400 MHz): δ 12.32 (br, 1H), 11.89 (br, 1H), 8.73 (d, J = 5.9 Hz, 1H), 7.62 (s, 1H), 7.51-7.48 (m, 2H), 7.24- 7.12 (m, 6H), 6.84 (d, J = 6.1 Hz, 1H), 4.01 (s, 6H), 3.78 (s, 2H), 2.28 (s, 3H) Ex. 2    93

ND^(c) (DMSO-d6, 400 MHz): δ 3.92 (s, 5H), 3.95 (s, 3H), 6.65 (d, J = 5.4 Hz, 1H), 7.06-7.50 (m, 7H), 7.99-8.05 (m, 1H), 8.55 (d, J = 5.1 Hz, 1H), 11.94 (s, 1H), 12.12 (s, 1H) Ex. 2    94

528 [M + H]+ (DMSO-d6, 400 MHz): δ 3.92 (s, 2H), 3.95 (s, 3H), 3.96 (s, 3H), 6.51 (d, J = 5.1 Hz, 1H), 7.04-7.12 (m, 2H), 7.20- 7.29 (m, 2H), 7.41-7.57 (m, 3H), 7.99- 8.05 (m, 1H), 8.52 (d, J = 5.1 Hz, 1H), 11.87 (s, 1H), 12.39 (s, 1H) Ex. 2    95

528 [M + H]+ (DMSO-d6, 400 MHz): δ 12.32 (br, 1H), 11.94 (br, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.02-7.99 (m, 1H), 7.54-7.41 (m, 4H), 7.15-7.11 (m, 3H), 6.49 (d, J = 5.4 Hz, 1H), 3.97 (s, 2H), 3.94 (s, 6H) Ex. 2    96

528 [M + H]+ (DMSO-d6, 400 MHz): δ 12.38 (br, 1H), 11.88 (br, 1H), 8.51 (d, J = 4.9 Hz, 1H), 8.02-7.99 (m, 1H), 7.53-7.19 (m, 7H), 6.50 (d, J = 5.1 Hz, 1H), 3.94 (s, 8H) Ex. 2    97

561 [M + H]+ (DMSO-d6, 400 MHz): δ 12.33 (br, 1H), 11.85 (br, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.06-7.93 (m, 4H), 7.63-7.43 (m, 4H), 6.46 (d, J = 5.1 Hz, 1H), 3.94 (s, 8H) Ex. 2    98

ND^(c) (CDCl3, 400 MHz): δ 3.64 (s, 2H), 4.04 (s, 3H), 4.05 (s, 3H), 6.53 (d, J = 5.1 Hz, 1H), 6.87-6.94 (m, 2H), 6.98-7.04 (m, 2H), 7.43 (s, 1H), 7.49 (s, 1H), 8.16-8.24 (m, 1H), 8.31-8.37 (m, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.81 (br, 1H), 9.04 (br, 1H) Ex. 6    99

ND^(c) (CDCl3, 400 MHz): δ 3.62 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.40 (d, J = 5.1 Hz, 1H), 6.87-6.96 (m, 2H), 7.20- 7.34 (m, 2H), 7.43 (s, 1H), 7.58 (s, 1H), 7.76-7.82 (m, 1H), 8.10-8.18 (m, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.72 (br, 1H), 9.38 (br, 1H) Ex. 6   100

458 [M + H]+ (DMSO-d6, 400 MHz): δ 3.49 (s, 2H), 3.92 (s, 3H), 3.93 (s, 3H), 6.44 (d, J = 5.4 Hz, 1H), 7.04-7.08 (m, 2H), 7.24 (d, J = 9.0 Hz, 2H), 7.28-7.34 (m, 2H), 7.38 (s, 1H), 7.50 (s, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 9.0 Hz, 2H), 8.45 (d, J = 5.4 Hz, 1H), 10.19 (s, 1H), 10.34 (s, 1H) Ex. 5   101

478 [M + H]+ (CDCl3, 400 MHz): δ 1.24-2.04 (m, 12H), 3.30 (s, 2H), 3.90-4.01 (m, 1H), 4.05 (s, 6H), 6.45 (d, J = 5.4 Hz, 1H), 7.14-7.17 (m, 2H), 7.42 (s, 1H), 7.55 (s, 1H), 7.65-7.68 (m, 2H), 8.48 (d, J = 5.1 Hz, 1H) Ex. 5   102

ND^(c) (CDCl3, 400 MHz): δ 3.60 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.47 (d, J = 5.4 Hz, 1H), 6.88-6.94 (m, 2H), 7.18 (d, J = 9.0 Hz, 2H), 7.45 (s, 1H), 7.55 (s, 1H), 7.68 (d, J =9.0 Hz, 2H), 8.14- 8.20 (m, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.78 (br, 1H), 8.91 (br, 1H) Ex. 5   103

524 [M + H]+ (CDCl3, 400 MHz): δ 3.81 (s, 3H), 4.05 (s, 3H), 4.07 (s, 3H), 4.50 (s, 1H), 6.48 (d, J = 5.6 Hz, 1H), 6.87-6.94 (m, 2H), 7.19 (d, J = 9.0 Hz, 2H), 7.52 (s, 1H), 7.55 (s, 1H), 7.70 (d, J = 9.0 Hz, 2H), 8.21-8.29 (m, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.79 (br, 1H), 8.93 (br, 1H) Ex. 15  104

522 [M + H]+ (CDCl3, 400 MHz): δ 1.73 (s, 6H), 4.05 (s, 3H), 4.05 (s, 3H), 6.44 (d, J = 5.1 Hz, 1H), 6.87-6.94 (m, 2H), 7.18 (d, J = 9.0 Hz, 2H), 7.43 (s, 1H), 7.55 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 8.14- 8.21 (m, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.56 (br, 1H), 8.70 (br, 1H) Ex. 15  105

472 [M − H]− (CDCl3, 400 MHz): δ 2.37 (s, 3H), 4.06 (s, 6H), 6.49 (d, J =5.1 Hz, 1H), 6.88 (d, J = 5.1 Hz, 1H), 7.2 (m, 2H), 7.43 (s, 1H), 7.58 (s, 1H), 7.7 (m, 2H), 8.2 (m, 2H), 8.49 (d, J = 5.2 Hz, 1H) Ex. 10  106 462 [M + H]+ (CDCl3, 400 MHz): δ 8.43 (d, 1H, J = Ex. 10^(b) 5.1 Hz), 7.82-7.79 (m, 1H), 7.49-7.08 (m, 12H), 6.36 (d, 1H, J = 5.1 Hz), 3.95 (s, 3H), 3.75 (s, 2H) ^(a))Synthesized as in Examples described below. ^(b))Synthesized as described in indicated Synthesis Example. ^(c))No data

Ex. No. Compound structure Starting compound A 107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

Ex. Mass spectrometric Synthesis No. Starting compound B Starting compound C value (m/z) method^(a) 107

496 [M + H]+ Ex. 3  108

476 [M + H]+ Ex. 3  109

458 [M + H]+ Ex. 3  110

487 [M + H]+ Ex. 8  111

485 [M + H]+ Ex. 8  112

487 [M + H]+ Ex. 8  113

496 [M + H]+ Ex. 7  114

514 [M + H]+ Ex. 7  115

514 [M + H]+ Ex. 7  116

516 [M + H]+ Ex. 7  117

488 [M + H]+ Ex. 8  118

463 [M + H]+ Ex. 3  119

545 [M + H]+ Ex. 8  120

573 [M + H]+ Ex. 8  121

517 [M + H]+ Ex. 8  122

517 [M + H]+ Ex. 8  123

483 [M + H]+ Ex. 8  124

490 [M + H]+ Ex. 3  125

476 [M + H]+ Ex. 3  126

494 [M + H]+ Ex. 3  127

494 [M + H]+ Ex. 3  128

511 [M + H]+ Ex. 3  129

490 [M + H]+ Ex. 7  130

528 [M + H]+ Ex. 7  131

517 [M + H]+ Ex. 8  132

512 [M + H]+ Ex. 3  133

512 [M + H]+ Ex. 3  134

512 [M + H]+ Ex. 3  135

512 [M + H]+ Ex. 3  136

544 [M + H]+ Ex. 3  137

544 [M + H]+ Ex. 3  138

512 [M + H]+ Ex. 3  139

512 [M + H]+ Ex. 3  140

512 [M + H]+ Ex. 3  141

512 [M + H]+ Ex. 3  142

512 [M + H]+ Ex. 3  143

470 [M + H]+ Ex. 2  144

508 [M + H]+ Ex. 2  145

528 [M + H]+ Ex. 2  146

557 [M + H]+ Ex. 2  147

476 [M + H]+ Ex. 1  148

478 [M + H]+ Ex. 1  149

522 [M + H]+ Ex. 2  150

500 [M + 1]+ Ex. 2  151

492 [M + H]+ Ex. 2  152

526 [M + H]+ Ex. 2  153

504 [M + 1]+ Ex. 2  154

539 [M + 1]+ Ex. 2  155

519 [M + 1]+ Ex. 2  156

353 [M + 1]+ Ex. 2  157

524 [M + 1]+ Ex. 2  158

488 [M + 1]+ Ex. 2  159

490 [M + 1]+ Ex. 2  160

480 [M + 1]+ Ex. 2  161

480 [M + 1]+ Ex. 1  162

488 [M + H]+ Ex. 1  163

502 [M + H]+ Ex. 1  164

492 [M + H]+ Ex. 2  165

474 [M + H]+ Ex. 2  166

498 [M + H]+ Ex. 2  167

488 [M + H]+ Ex. 2  168

488 [M + H]+ Ex. 2  169

522 [M + H]+ Ex. 2  170

506 [M + H]+ Ex. 2  171

506 [M + H]+ Ex. 2  172

526 [M + H]+ Ex. 2  173

526 [M + H]+ Ex. 2  174

542 [M + H]+ Ex. 2  175

506 [M + H]+ Ex. 2  176

506 [M + H]+ Ex. 2  177

468 [M + H]+ Ex. 2  178

486 [M + H]+ Ex. 2  179

486 [M + H]+ Ex. 2  180

476 [M + H]+ Ex. 2  181

522 [M + H]+ Ex. 2  182

526 [M + H]+ Ex. 2  183

543 [M + H]+ Ex. 2  184

504 [M + H]+ Ex. 2  185

522 [M + H]+ Ex. 2  186

539 [M + H]+ Ex. 2  187

508 [M + H]+ Ex. 2  188

526 [M + H]+ Ex. 2  189

543 [M + H]+ Ex. 2  190

506 [M + H]+ Ex. 2  191

512 [M + H]+ Ex. 2  192

512 [M + H]+ Ex. 2  193

505 [M + H]+ Ex. 2  194

528 [M + H]+ Ex. 2  195

528 [M + H]+ Ex. 2  196

528 [M + H]+ Ex. 2  197

528 [M + H]+ Ex. 2  198

528 [M + H]+ Ex. 2  199

528 [M + H]+ Ex. 2  200

560 [M + H]+ Ex. 2  201

560 [M + H]+ Ex. 2  202

560 [M + H]+ Ex. 2  203

560 [M + H]+ Ex. 2  204

528 [M + H]+ Ex. 2  205

546 [M + H]+ Ex. 2  206

546 [M + H]+ Ex. 2  207

562 [M + H]+ Ex. 2  208

561 [M + H]+ Ex. 2  209

438 [M + H]+ Ex. 5  210

492 [M + H]+ Ex. 5  211

488 [M + H]+ Ex. 5  212

436 [M + H]+ Ex. 5  213

516 [M + H]+ Ex. 5  214

486 [M + H]+ Ex. 5  215

472 [M + H]+ Ex. 5  216

472 [M + H]+ Ex. 5  217

464 [M + H]+ Ex. 5  218

478 [M + H]+ Ex. 5  219

492 [M + H]+ Ex. 5  220

474 [M + H]+ Ex. 5  221

466 [M + H]+ Ex. 5  222

528 [M + H]+ Ex. 6  223

508 [M + H]+ Ex. 6  224

522 [M + H]+ Ex. 6  225

472 [M + H]+ Ex. 15 226

478 [M + H]+ Ex. 15 227

459 [M + H]+ Ex. 5  228

486 [M + H]+ Ex. 15 229

493 [M − H]− Ex. 9  230

550 [M − H]− Ex. 9  231

492 [M − H]− Ex. 9  232

462 [M − H]− Ex. 9  233

472 [M − H]− Ex. 9  234

472 [M − H]− Ex. 9  235

472 [M − H]− Ex. 9  236

458 [M − H]− Ex. 9  237

461 [M − H]− Ex. 9  238

515 [M − H]− Ex. 9  239

482 [M − H]− Ex. 9  240

525 [M − H]− Ex. 9  241

496 [M − H]− Ex. 9  242

505 [M − H]− Ex. 9  243

497 [M − H]− Ex. 9  244

487 [M − H]− Ex. 9  245

515 [M − H]− Ex. 9  246

547 [M − H]− Ex. 9  247

535 [M − H]− Ex. 9  248

491 [M − H]− Ex. 9  249

491 [M − H]− Ex. 9  250

509 [M − H]− Ex. 9  251

475 [M − H]− Ex. 9  252

475 [M − H]− Ex. 9  253

503 [M − H]− Ex. 9  254

502 [M − H]− Ex. 9  255

549 [M − H]− Ex. 9  256

471 [M − H]− Ex. 9  257

571 [M − H]− Ex. 9  258

485 [M − H]− Ex. 9  259

522 [M − H]− Ex. 9  260

508 [M − H]− Ex. 9  261

499 [M − H]− Ex. 9  262

508 [M − H]− Ex. 9  263

525 [M − H]− Ex. 9  264

493 [M − H]− Ex. 9  265

493 [M − H]− Ex. 9  266

487 [M − H]− Ex. 9  267

501 [M − H]− Ex. 9  ^(a))Synthesized as in Examples described below.

Example 277 1-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluorophenyl)-acetyl]-thiourea 1) Synthesis of 3-fluoro-4-[(7-(3-bromoethyl)-6-methoxy-4-quinolyl)oxy]aniline)

3-Fluoro-4-[(7-benzyloxy-6-methoxy-4-quinolyl)-oxy]aniline (7.8 g), together with trifluoroacetic acid (80 ml) and methanesulfonic acid (1 ml), was stirred at 80° C. for 2 hr. After the removal of the solvent by evaporation, the residue was neutralized with an aqueous saturated sodium hydrogencarbonate solution, and the precipitated crystal was collected by suction filtration to give a crude crystal (8.8 g) (starting compound A). This crude crystal (5 g) was dissolved in dimethylformamide (120 ml). Potassium carbonate (9.2 g) and dibromoethane (12.5 g) (starting compound C) were added to the solution, and the mixture was stirred at room temperature for about 90 hr. The reaction solution was filtered through Celite, and the solvent was removed from the filtrate by evaporation under the reduced pressure. The residue was purified by column chromatography on silica gel [chloroform:methanol] to give 3-fluoro-4-[(7-(3-bromoethyl)-6-methoxy-4-quinolyl)oxy]aniline) (1.88 g, yield 29%).

2) Synthesis of 1-{3-fluoro-4-[7-(3-bromoethyl)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

4-Fluorophenylacetic acid (2.37 g) (starting compound D) was dissolved in thionyl chloride (8 ml) to prepare a solution which was then stirred at 40° C. for one hr. The solvent was removed by evaporation under the reduced pressure. Acetonitrile (300 ml) was added to the residue to dissolve the residue. Potassium thiocyanate (1.87 g) was added to the solution, and the mixture was stirred at 40° C. for 50 min. The solvent was removed by evaporation under the reduced pressure. Ethyl acetate (50 ml) and an aqueous saturated sodium hydrogencarbonate solution (50 ml) were added to the residue, and the mixture was stirred at room temperature for 10 min. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was dissolved in ethanol:toluene (1:1=10 ml). 3-Fluoro-4-[(7-(3-bromoethyl)-6-methoxy-4-quinolyl)oxy]aniline (1.4 g) synthesized in step 1) was added to the solution, and the mixture was stirred at room temperature for 18 hr. The precipitated crystal was collected by filtration to give the title compound (1.58 g, yield 73%).

¹H-NMR (DMSO, 400 MHz): δ 3.85 (s, 2H), 3.96 (t, J=5.4 Hz, 2H), 4.06 (s, 3H), 4.62 (t, J=5.4 Hz, 2H), 6.98 (d, J=6.3 Hz, 1H), 7.15-7.23 (m, 2H), 7.37-7.43 (m, 2H), 7.55 (s, 1H), 7.60-7.68 (m, 1H), 7.79 (s, 1H), 8.15-8.18 (m, 1H), 8.85 (d, J=6.3 Hz, 1H), 11.86 (s, 1H), 12.54 (s, 1H)

3) Synthesis of 1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluorophenyl)-acetyl]-thiourea (Example 277)

Dimethylformamide (3 ml) was added to the compound (200 mg) prepared in step 2) to dissolve the compound. Morpholine (29 mg) (starting compound B) and potassium carbonate (46 mg) were added to the solution, and the mixture was stirred at room temperature for 18 hr. Ethyl acetate:water was added thereto, and the mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was purified by TLC preparation [chloroform:methanol] to give the title compound (Example 277) (92 mg, yield 46%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.89 (s, 4H), 2.95 (s, 4H), 3.73 (s, 2H), 3.73-3.78 (m, 2H), 4.03 (s, 3H), 4.34 (t, J=6.1 Hz, 2H), 6.43 (d, J=5.1 Hz, 1H), 7.12 (t, J=8.8 Hz, 1H), 7.23-7.32 (m, 6H), 7.43 (s, 1H), 7.94 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.66 (br, 1H), 12.44 (s, 1H)

ESI-MS: m/z=607 (M−1)

Example 285 1-[2-(2-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-thiourea

2-Chlorophenylacetic acid (96 mg) (starting compound D) was dissolved in thionyl chloride (0.5 ml) to prepare a solution which was then stirred at 40° C. for one hr. The solvent was removed by evaporation under the reduced pressure. Acetonitrile (30 ml) was added to the residue to dissolve the residue. Potassium thiocyanate (68 mg) was added to the solution, and the mixture was stirred at 40° C. for 50 min. The solvent was removed by evaporation under the reduced pressure. Ethyl acetate (15 ml) and an aqueous saturated sodium hydrogencarbonate solution (15 ml) were added to the residue, and the mixture was stirred at room temperature for 20 min. The reaction solution was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was dissolved in ethanol:toluene (1:1=6 ml). Starting compound 12 (60 mg) (starting compound A) was added to the solution, and the mixture was stirred at room temperature for 18 hr. The solvent was removed by evaporation under the reduced pressure, and the residue was purified by TLC preparation [chloroform:methanol] to give the title compound (44 mg, yield 49%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.10-2.18 (m, 2H), 2.47-2.54 (m, 4H), 2.59 (t, J=7.2 Hz, 2H), 3.73 (t, J=4.5 Hz, 4H), 3.89 (s, 2H), 4.03 (s, 3H), 4.28 (t, J=6.7 Hz, 2H), 6.44 (dd, J=1.0, 5.4 Hz, 1H), 7.31-7.52 (m, 6H), 7.54 (s, 1H), 7.95 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.64 (s, 1H), 12.42 (s, 1H)

ESI-MS: m/z=639 (M+1), 637 (M−1)

Example 287 1-{2-Fluoro-4-[(6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenyl-acetyl-urea 1) Synthesis of 2-fluoro-4-[(7-(3-chloropropyl)-6-methoxy-4-quinolyl)oxy]aniline)

2-Fluoro-4-[(7-benzyloxy-6-methoxy-4-quinolyl)-oxy]aniline (4.2 g) (starting compound 2), together with trifluoroacetic acid (20 ml) and methanesulfonic acid (1 ml), was heated under reflux for one hr. The solvent was removed by evaporation, and the residue was then neutralized with a 10% aqueous sodium hydroxide solution. The precipitated crystal was collected by suction filtration to give a crude crystal (3.8 g) (starting compound A). This crude crystal (2 g) was dissolved in dimethylformamide (80 ml). Potassium carbonate (4.9 g) and 1-bromo-3-chloro-propane (5.6 g) (starting compound C) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography on silica gel, and the title compound (1.65 g, yield 77%) was obtained from the fraction of chloroform:methanol (99:1).

¹H-NMR (CDCl₃, 400 MHz): δ 2.36-2.43 (m, 2H), 3.75 (s, 2H), 3.79-3.83 (m, 2H), 3.96 (s, 3H), 4.32-4.36 (m, 2H), 6.44 (d, J=5.3 Hz, 1H), 6.80-6.92 (m, 3H), 7.43 (s, 1H), 7.52 (s, 1H), 8.48 (d, J=5.3 Hz, 1H)

2) Synthesis of 2-fluoro-4-[(6-methoxy-7-(3-morpholinopropyl)-4-quinolyl)oxy]aniline

The aniline compound (0.7 g) prepared in step 1) was dissolved in dimethylformamide (40 ml) to prepare a solution. Potassium carbonate (1.4 g), sodium iodide (0.6 g) and morpholine (0.85 g) (starting compound B) were added to the solution, and the mixture was stirred at 70° C. for 20 hr. The reaction solution was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography on silica gel, and the title compound (0.64 g, yield 76%) was obtained from the fraction of chloroform:methanol (95:5).

¹H-NMR (CDCl₃, 400 MHz): δ 2.01-2.11 (m, 2H), 2.37-2.50 (m, 4H), 2.44-2.57 (m, 2H), 3.64-3.74 (m, 4H), 3.67 (s, 2H), 3.95 (s, 3H), 4.13-4.22 (m, 2H), 6.36 (d, J=5.4 Hz, 1H), 6.73-6.84 (m, 3H), 7.35 (s, 1H), 7.46 (s, 1H), 8.40 (d, J=5.4 Hz, 1H)

3) Synthesis of 1-{2-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenyl-acetyl-urea (Example 287)

Phenylacetamide (95 mg) (starting compound D) was suspended in anhydrous dichloroethane (10 ml). Oxalyl chloride (0.09 ml) was added to the suspension, and the mixture was heated under reflux for 17 hr. The solvent was removed by evaporation under the reduced pressure to give a crude crystal. The crude crystal was suspended in anhydrous chloroform (10 ml). The suspension was added at room temperature to a solution of the aniline compound (100 mg) prepared in step 2) and triethylamine (330 mg) in anhydrous chloroform (10 ml), and the mixture was stirred at room temperature for 5 hr. A 2% aqueous sodium hydroxide solution was added thereto, and the chloroform layer was separated. The separated chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography on silica gel, and the title compound (Example 287) (115 mg, yield 84%) was obtained from the fraction of chloroform:methanol (97:3).

¹H-NMR (CDCl₃, 400 MHz): δ 2.07-2.15 (m, 2H), 2.44-2.51 (m, 4H), 2.55 (t, J=7.0 Hz, 2H), 3.69-3.75 (m, 4H), 3.75 (s, 2H), 3.98 (s, 3H), 4.24 (t, J=6.5 Hz, 2H), 6.48 (d, J=5.1 Hz, 1H), 6.94-7.00 (m, 4H), 7.24-7.40 (m, 5H), 7.36 (s, 1H), 7.40 (s, 1H), 8.18 (t, J=8.8 Hz, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 10.76 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 589 (M⁺+1)

Example 313 1-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluorophenyl)-acetyl]-thiourea

1) Synthesis of 1-{[4-(4-aminophenoxy)-6-methoxy-7-quinolyl]oxy}-3-morpholino-2-propanol

Starting compound 2 (10 g), together with trifluoroacetic acid (100 ml) and methanesulfonic acid (1 ml), was heated under reflux for one hr. The temperature of the reaction solution was returned to room temperature, and the solvent was removed by evaporation. The residue was then made weakly alkaline with an aqueous saturated sodium hydrogencarbonate solution to precipitate a solid. The solid was collected by filtration, was washed with water, and was then dried to give a crude crystal (9.6 g) (starting compound A). Dimethylformamide (300 ml) was added to the crude crystal to dissolve the crystal. Potassium carbonate (23.5 g) and epibromohydrin (3.1 ml) (starting compound C) were then added to the solution, and the mixture was stirred at room temperature overnight. Further, potassium carbonate (2.3 g) and epibromohydrin (0.3 ml) (starting compound C) were added thereto, and the mixture was stirred at room temperature overnight. Morpholine (14.8 ml) (starting compound B) was added thereto, and the mixture was stirred at 70° C. overnight. The temperature of the reaction solution was returned to room temperature, and water was added thereto. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over sodium sulfate, and the dried organic layer was then concentrated. The residue was purified by column chromatography on silica gel using chloroform:methanol for development to give 6.9 g of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 2.48-2.54 (m, 2H), 2.62-2.64 (m, 2H), 2.67-2.73 (m, 2H), 3.52 (brs, 1H), 3.73-3.76 (m, 4H), 3.82 (brs, 2H), 4.16-4.23 (m, 2H), 4.26-4.32 (m, 1H), 6.42 (dd, J=1.0, 5.4 Hz, 1H), 6.50 (ddd, J=1.0, 2.7, 8.5 Hz, 1H), 6.57 (dd, J=2.7, 12.0 Hz, 1H), 7.04 (t, J=8.5 Hz, 1H), 7.45 (s, 1H), 7.58 (s, 1H), 8.47 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI-MS, m/z): 442 (M⁺−1)

2) 1-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea (Example 313)

4-Fluorophenylacetic acid (4.3 g) (starting compound D) was added to thionyl chloride (10 ml). The mixture was stirred at 40° C. for one hr and was then concentrated, and the residue was then dried by means of a vacuum pump. Acetonitrile (250 ml) was added thereto, and potassium isothiocyanate (3.4 g) was added to the mixture. The mixture was stirred at 40° C. for 50 min, followed by concentration. An aqueous saturated sodium hydrogencarbonate solution was added to the concentrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over sodium sulfate, and the solvent was then removed by evaporation. A mixed solvent composed of toluene (50 ml) and ethanol (50 ml) was added to the residue, and amine (3.0 g) was added thereto. The mixture was stirred at room temperature overnight. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with a mixed solvent composed of chloroform and methanol. The organic layer was washed with saturated brine and was dried over sodium sulfate. The dried organic layer was then concentrated, and the residue was purified by column chromatography on silica gel using chloroform:methanol for development to give the title compound (1.4 g, yield 44%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.48-2.55 (m, 2H), 2.60-2.73 (m, 4H), 3.72-3.77 (m, 6H), 4.02 (s, 3H), 4.16-4.32 (m, 3H), 6.45 (d, J=4.4 Hz, 1H), 7.12 (t, J=8.5 Hz, 2H), 7.23-7.32 (m, 3H), 7.40 (d, J=8.8 Hz, 1H), 7.45 (s, 1H), 7.54 (s, 1H), 7.93 (dd, J=2.6, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.65 (s, 1H), 12.44 (s, 1H)

ESI-MS: m/z=639 (M+1)

Compounds of Examples 277, 285, 287, and 313 had the following respective structures.

Compounds of Examples 270 to 276, 278 to 284, 286, 288 to 312, and 314 to 337 were synthesized as described in Examples 277, 285, 287, and 313. For these compounds, chemical structural formulae, starting compounds, synthesis methods, and data for identifying the compounds are as follows.

Ex. No. Compound structure 270

271

272

273

275

276

277

278

279

282

283

284

286

288

289

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

Ex. No. Starting compound A Starting compound B 270

271

272

273

275

276

277

278

279

282

283

284

286

288

289

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

Ex. Synthesis No. Starting compound C Starting Compound D method^(a) 270

Ex. 277 271

Ex. 277 272

Ex. 277 273

Ex. 277 275

Ex. 277 276

Ex. 277 277

Ex. 277 278

Ex. 277 279

Ex. 277 282

Ex. 277 283

Ex. 287 284

Ex. 277 286

Ex. 287 288

Ex. 285 289

Ex. 285 291

Ex. 287 292

Ex. 287 293

Ex. 287 294

Ex. 287 295

Ex. 287 296

Ex. 287 297

Ex. 277 298

Ex. 277 299

Ex. 277 300

Ex. 277 301

Ex. 277 302

Ex. 285 303

Ex. 285 304

Ex. 285 305

Ex. 287 306

Ex. 287 307

Ex. 277 308

Ex. 287 309

Ex. 277 310

Ex. 277 311

Ex. 287 312

Ex. 313 314

Ex. 313 315

Ex. 313 316

Ex. 313 317

Ex. 313 318

Ex. 313 319

Ex. 313 320

Ex. 313 321

Ex. 313 322

Ex. 313 323

Ex. 313 324

Ex. 313 325

Ex. 313 326

Ex. 313 327

Ex. 313 328

Ex. 313 329

Ex. 313 330

Ex. 285 331

Ex. 285 332

Ex. 285 333

Ex. 285 334

Ex. 285 335

Ex. 285 336

Ex. 287 337

Ex. 287

Example 270 1-(3-Fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea

¹H-NMR (DMSO, 400 MHz): δ 2.20 (s, 3H), 2.33-2.57 (m, 8H), 2.79 (t, J=5.6 Hz, 2H), 3.83 (s, 2H), 3.94 (s, 3H), 4.26 (t, J=5.9 Hz, 2H), 6.48 (d, J=5.1 Hz, 1H), 7.23-7.57 (m, 9H), 8.01 (dd, J=2.2, 12.2 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 11.82 (br, 1H), 12.50 (br, 1H)

ESI-MS: m/z=604 (M+1), 602 (M−1)

Example 271 1-(3-Fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 2.16 (s, 3H), 2.28-2.62 (m, 8H), 2.78 (t, J=5.9 Hz, 2H), 3.83 (s, 2H), 3.94 (s, 3H), 4.26 (t, J=5.9 Hz, 2H), 6.48 (dd, J=1.0, 5.1 Hz, 1H), 7.10-7.41 (m, 6H), 7.44 (s, 1H), 7.52 (s, 1H), 8.00 (dd, J=2.2, 12.2 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 11.81 (br, 1H), 12.47 (br, 1H)

Example 272 1-{4-[7-(2-Diethylamine-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-phenylacetyl-thiourea

¹H-NMR (DMSO-d₆, 400 MHz): δ 1.01 (t, J=7.1 Hz, 6H), 2.50-2.70 (m, 4H), 2.80-3.00 (m, 2H), 3.81 (s, 2H), 3.92 (s, 3H), 4.20 (t, J=5.9 Hz, 2H), 6.46 (d, J=5.1 Hz, 1H), 7.07-7.57 (m, 9H), 7.93-8.10 (m, 1H), 8.48 (d, J=5.1 Hz, 1H), 11.80 (s, 1H), 12.50 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 577 (M+1)⁺

Example 273 1-(3-Fluoro-4-{6-methoxy-7-[2-(4-methyl-[1,4]diazepan-1-yl)-ethoxy]-3-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.84-1.94 (m, 2H), 2.42 (s, 3H), 2.68-2.78 (m, 4H), 2.88-2.97 (m, 4H), 3.12 (t, J=6.4 Hz, 2H), 3.76 (s, 2H), 4.02 (s, 3H), 4.29 (t, J=6.4 Hz, 2H), 6.44 (d, J=5.1 Hz, 1H), 7.24-7.49 (m, 8H), 7.54 (s, 1H), 7.93 (dd, J=2.4, 11.7 Hz, 1H), 8.51 (d, J=5.1 Hz, 1H)

ESI-MS: m/z=618 (M+1), 616 (M−1)

Example 275 1-{4-[7-(2-Diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 1.11 (t, J=7.1 Hz, 6H), 2.66-2.74 (m, 4H), 3.02-3.08 (m, 2H), 3.73 (s, 2H), 4.02 (s, 3H), 4.29 (t, J=6.5 Hz, 2H), 6.44 (d, J=5.1 Hz, 1H), 7.09-7.46 (m, 7H), 7.53 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.51 (br, 1H), 12.42 (s, 1H)

ESI-MS: m/z=595 (M+1), 593 (M−1)

Example 276 1-{3-Fluoro-4-[(6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.62-2.72 (m, 4H), 2.98 (t, J=5.7 Hz, 2H), 3.70-3.78 (m, 6H), 4.02 (s, 3H), 4.35 (t, J=5.7 Hz, 2H), 6.46 (d, J=5.4 Hz, 1H), 7.21-7.45 (m, 8H), 7.55 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H), 8.52 (d, J=5.4 Hz, 1H), 9.33 (s, 1H), 12.57 (s, 1H)

ESI-MS: m/z=591 (M+1), 589 (M−1)

Example 278 1-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.63-2.78 (m, 4H), 2.98 (t, J=5.8 Hz, 2H), 3.75-3.82 (m, 4H), 3.80 (s, 2H), 4.03 (s, 3H), 4.37 (t, J=5.8 Hz, 2H), 6.46 (d, J=5.4 Hz, 1H), 7.05-7.43 (m, 6H), 7.47 (s, 1H), 7.55 (s, 1H), 7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.92 (s, 1H), 12.45 (s, 1H)

ESI-MS: m/z=607 (M−1)

Example 279 1-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.66-3.06 (m, 6H), 3.70-3.85 (m, 6H), 4.03 (s, 3H), 4.39 (t, J=5.8 Hz, 2H), 6.48 (d, J=5.4 Hz, 1H), 7.04-7.14 (m, 3H), 7.25-7.45 (m, 3H), 7.50 (s, 1H), 7.56 (s, 1H), 7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.74 (s, 1H), 12.44 (s, 1H)

ESI-MS: m/z=607 (M−1)

Example 282 1-(3-Fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.58-1.99 (m, 5H), 2.43-2.62 (m, 2H), 3.16-3.40 (m, 4H), 3.50-3.54 (m, 2H), 3.73 (s, 2H), 4.03 (s, 3H), 4.45-4.51 (m, 2H), 6.47 (d, J=5.4 Hz, 1H), 7.06-7.15 (m, 2H), 7.22-7.34 (m, 4H), 7.42 (s, 1H), 7.57 (s, 1H), 7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=637 (M+1), 635 (M−1)

Example 283 1-(3-Fluoro-4-{7-[(2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.13-1.76 (m, 7H), 2.11-2.26 (m, 2H), 2.87-3.11 (m, 4H), 3.37-3.48 (m, 2H), 3.70 (s, 2H), 3.95 (s, 3H), 4.26-4.33 (m, 2H), 6.32 (d, J=5.1 Hz, 1H), 7.07-7.50 (m, 7H), 7.35 (s, 1H), 7.48 (s, 1H), 7.57-7.65 (m, 1H), 8.13 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 10.59 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 603 (M+1)

Example 284 1-(3-Fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea

¹H-NMR (CDCl₃:CD₃OD=10:1, 400 MHz): δ 1.45-1.88 (m, 5H), 2.37-2.50 (m, 2H), 3.08-3.18 (m, 2H), 3.26-3.34 (m, 2H), 3.50-3.54 (m, 2H), 3.76 (s, 2H), 4.02 (s, 3H), 4.41-4.47 (m, 2H), 6.47 (d, J=5.1 Hz, 1H), 7.22-7.47 (m, 7H), 7.56 (s, 1H), 7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.48 (d, J=5.1 Hz, 1H)

ESI-MS: m/z=619 (M+1), 617 (M−1)

Example 286 1-{2-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 2.02-2.25 (m, 2H), 2.40-2.49 (m, 4H), 2.51 (t, J=7.1 Hz, 2H), 3.64-3.67 (m, 4H), 3.67 (s, 2H), 3.93 (s, 3H), 4.19 (t, J=6.7 Hz, 2H), 6.44 (d, J=5.4 Hz, 1H), 6.89-7.02 (m, 4H), 7.20-7.25 (m, 2H), 7.36 (s, 1H), 7.39 (s, 1H), 8.13 (t, J=8.5 Hz, 1H), 8.43 (d, J=5.4 Hz, 1H), 9.30 (s, 1H), 10.74 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 607 (M⁺+1)

Example 288 1-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.12-2.19 (m, 2H), 2.50-2.66 (m, 6H), 3.72-3.81 (m, 6H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.45 (d, J=5.4 Hz, 1H), 7.16-7.42 (m, 6H), 7.45 (s, 1H), 7.54 (s, 1H), 7.94 (dd, J=2.4, 11.5 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.61 (s, 1H), 12.41 (s, 1H)

ESI-MS: m/z=623 (M+1), 621 (M−1)

Example 289 1-{3-Fluoro-4-[(6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.10-2.18 (m, 2H), 2.44-2.56 (m, 4H), 2.59 (t, J=7.2 Hz, 2H), 3.70-3.76 (m, 6H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.45 (d, J=5.4 Hz, 1H), 7.01-7.13 (m, 3H), 7.26-7.44 (m, 3H), 7.44 (s, 1H), 7.54 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.55 (s, 1H), 12.41 (s, 1H)

ESI-MS: m/z=623 (M+1), 621 (M−1)

Example 291 1-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-phenylacetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.31 (t, J=7.3 Hz, 6H), 2.29-2.39 (m, 2H), 2.93-3.02 (m, 4H), 3.06-3.17 (m, 2H), 3.80 (s, 2H), 4.01 (s, 3H), 4.26 (t, J=6.0 Hz, 2H), 6.38 (d, J=5.1 Hz, 1H), 7.18-7.44 (m, 8H), 7.56 (s, 1H), 7.68 (dd, J=2.4, 12.2 Hz, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.85 (br, 1H), 10.72 (s, 1H)

ESI-MS: m/z=575 (M+1)

Example 292 1-{3-Fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.94-2.05 (m, 4H), 2.30-2.40 (m, 2H), 2.80-3.15 (m, 6H), 3.78 (s, 2H), 4.02 (s, 3H), 4.27 (t, J=6.1 Hz, 2H), 6.38 (d, J=1.0, 5.4 Hz, 1H), 7.16-7.44 (m, 8H), 7.56 (s, 1H), 7.68 (dd, J=2.4, 12.7 Hz, 1H), 8.45 (br, 1H), 8.47 (d, J=5.4 Hz, 1H), 10.69 (s, 1H)

Example 293 1-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.27 (t, J=7.2 Hz, 6H), 2.25-2.35 (m, 2H), 2.87-3.10 (m, 6H), 3.84 (s, 2H), 4.01 (s, 3H), 4.26 (t, J=6.1 Hz, 2H), 6.38 (d, J=5.4 Hz, 1H), 7.10-7.25 (m, 4H), 7.29-7.40 (m, 2H), 7.41 (s, 1H), 7.56 (s, 1H), 7.67 (dd, J=2.2, 12.7 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H), 8.91 (br, 1H), 10.67 (s, 1H)

ESI-MS: m/z=593 (M+1)

Example 294 1-{3-Fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.93-2.00 (m, 4H), 2.28-2.36 (m, 2H), 2.75-3.09 (m, 6H), 3.83 (s, 2H), 4.02 (s, 3H), 4.27 (t, J=6.3 Hz, 2H), 6.38 (dd, J=1.0, 5.1 Hz, 1H), 7.10-7.28 (m, 4H), 7.30-7.39 (m, 2H), 7.41 (s, 1H), 7.55 (s, 1H), 7.68 (dd, J=2.2, 11.7 Hz, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.85 (br, 1H), 10.66 (s, 1H)

ESI-MS: m/z=593 (M+1)

Example 295 1-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.45-1.55 (m, 2H), 1.68-1.79 (m, 4H), 2.09-2.16 (m, 2H), 2.54-2.82 (m, 6H), 3.83 (s, 2H), 4.02 (s, 3H), 4.25 (t, J=6.6 Hz, 2H), 6.38 (dd, J=0.7, 5.4 Hz, 1H), 7.10-7.31 (m, 4H), 7.30-7.39 (m, 2H), 7.41 (s, 1H), 7.55 (s, 1H), 7.68 (dd, J=2.2, 12.7 Hz, 1H), 8.46 (d, J=5.4 Hz, 1H), 9.00 (br, 1H), 10.68 (s, 1H)

ESI-MS: m/z=605 (M+1)

Example 296 1-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-[2-(2-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 2.08-2.17 (m, 2H), 2.28-2.70 (m, 13H), 3.81 (s, 2H), 4.03 (s, 3H), 4.23-4.39 (m, 2H), 6.39 (d, J=5.4 Hz, 1H), 7.12-7.23 (m, 4H), 7.17-7.40 (m, 2H), 7.43 (s, 1H), 7.55 (s, 1H), 7.69 (dd, J=2.2, 12.1 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H), 8.70 (br, 1H), 10.65 (s, 1H)

Example 297 1-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-(2-m-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.08-2.17 (m, 2H), 2.32-2.44 (m, 5H), 2.52-2.65 (m, 8H), 3.71 (s, 2H), 4.02 (s, 3H), 4.26 (t, J=6.3 Hz, 2H), 6.44 (d, J=5.4 Hz, 1H), 7.01-7.55 (m, 8H), 7.93 (dd, J=2.7, 11.5 Hz, 1H), 8.48-8.54 (m, 2H), 12.49 (s, 1H)

ESI-MS: m/z=632 (M+1)

Example 298 1-{3-Chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.15-2.22 (m, 2H), 2.52-2.58 (m, 4H), 2.63 (t, J=7.1 Hz, 2H), 3.76 (t, J=4.6 Hz, 4H), 3.80 (s, 2H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.38 (d, J=5.1 Hz, 1H), 7.13-7.25 (m, 3H), 7.29-7.42 (m, 2H), 7.46 (s, 1H), 7.55 (s, 1H), 7.62 (dd, J=2.4, 8.8 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H) 8.97 (s, 1H), 12.39 (s, 1H)

ESI-MS: m/z=639 (M+1)

Example 299 1-{3-Chloro-4-[6-methoxy-7-(3-morpholin-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.15-2.26 (m, 2H), 2.55-2.75 (m, 6H), 3.77 (s, 2H), 3.78-3.83 (m, 4H), 4.03 (s, 3H), 4.29 (t, J=6.6 Hz, 2H), 6.39 (d, J=5.1 Hz, 1H), 7.02-7.13 (m, 4H), 7.36-7.44 (m, 1H), 7.48 (s, 1H), 7.55 (s, 1H), 7.62 (dd, J=2.4, 8.8 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.85 (s, 1H), 12.39 (s, 1H)

ESI-MS: m/z=639 (M+1)

Example 300 1-{3-Chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.14-2.24 (m, 2H), 2.53-2.72 (m, 6H), 3.76-3.80 (m, 6H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.38 (d, J=5.4 Hz, 1H), 7.22-7.45 (m, 7H), 7.55 (s, 1H), 7.62 (dd, J=2.4, 8.8 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.72 (s, 1H), 12.44 (s, 1H)

ESI-MS: m/z=621 (M+1)

Example 301 1-{3-Chloro-4-[6-methoxy-7-(3-morpholin-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃:CD₃OD=30:1, 400 MHz): δ 2.20-2.32 (m, 2H), 2.36 (s, 3H), 2.72-2.90 (m, 6H), 3.78 (s, 2H), 3.80-3.85 (m, 4H), 4.04 (s, 3H), 4.36 (t, J=6.1 Hz, 2H), 6.41 (d, J=5.4 Hz, 1H), 7.21-7.33 (m, 5H), 7.54-7.61 (m, 2H), 7.65 (dd, J=2.4, 8.6 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 8.45 (br, 1H), 9.00 (br, 1H), 12.50 (br, 1H)

ESI-MS: m/z=635 (M+1)

Example 302 1-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.20-2.33 (m, 2H), 2.36 (s, 3H), 2.50-2.59 (m, 6H), 3.79 (s, 2H), 3.81-3.90 (m, 4H), 4.03 (s, 3H), 4.29 (t, J=6.3 Hz, 2H), 6.47 (d, J=5.4 Hz, 1H), 7.22-7.34 (m, 5H), 7.42 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 7.55 (s, 1H), 7.96 (dd, J=2.4, 11.7 Hz, 1H), 8.44 (br, 1H), 8.50 (d, J=5.4 Hz, 1H), 12.52 (s, 1H)

ESI-MS: m/z=619 (M+1)

Example 303 1-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.10-2.20 (m, 2H), 2.39 (s, 3H), 2.55-2.67 (m, 6H), 3.71 (s, 2H), 3.75-3.80 (m, 4H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.46 (d, J=4.6 Hz, 1H), 7.08-7.36 (m, 5H), 7.41 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.55 (s, 1H), 7.91-8.01 (m, 1H), 8.48-8.54 (m, 1H), 8.96 (br, 1H), 12.53 (s, 1H)

ESI-MS: m/z=619 (M+1)

Example 304 1-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-p-toluyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.14-2.24 (m, 2H), 2.38 (s, 3H), 2.55-2.72 (m, 6H), 3.72 (s, 2H), 3.76-3.82 (m, 4H), 4.03 (s, 3H), 4.28 (t, J=6.4 Hz, 2H), 6.46 (d, J=5.4 Hz, 1H), 7.16-7.28 (m, 5H), 7.40 (d, J=8.8 Hz, 1H), 7.46 (s, 1H), 7.54 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.64 (s, 1H), 12.52 (s, 1H)

ESI-MS: m/z=619 (M+1)

Example 305 1-{3-Fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-urea

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.19-2.38 (m, 2H), 3.74 (s, 2H), 3.97 (s, 3H), 4.09 (t, J=6.3 Hz, 2H), 4.19 (t, J=6.8 Hz, 2H), 6.44 (d, J=5.4 Hz, 1H), 6.89 (s, 1H), 7.15-7.50 (m, 9H), 7.54 (s, 1H), 7.64 (s, 1H), 7.76-7.88 (m, 1H), 8.47 (d, J=5.4 Hz, 1H), 10.64 (s, 1H), 11.05 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 570 (M+1)⁺

Example 306 1-{3-Fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.20-2.40 (m, 2H), 3.85 (s, 2H), 3.97 (s, 3H), 4.05-4.15 (m, 2H), 4.15-4.26 (m, 2H), 6.45 (d, J=5.1 Hz, 1H), 6.90 (s, 1H), 7.08-7.50 (m, 8H), 7.54 (s, 1H), 7.64 (s, 1H), 7.77-7.90 (m, 1H), 8.47 (d, J=5.1 Hz, 1H), 10.57 (s, 1H), 11.08 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 588 (M+1)⁺

Example 307 1-{3-Fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.21-2.39 (m, 2H), 3.83 (s, 2H), 3.97 (s, 3H), 4.00-4.20 (m, 2H), 4.15-4.30 (m, 2H), 6.50 (d, J=5.3 Hz, 1H), 6.91 (s, 1H), 7.17-7.60 (m, 10H), 7.70 (s, 1H), 7.95-8.07 (m, 1H), 8.49 (d, J=5.3 Hz, 1H), 11.80 (s, 1H), 12.51 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 586 (M+1)⁺

Example 308 1-(3-Fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.22-2.43 (m, 9H), 2.50-2.65 (m, 2H), 2.98-3.12 (m, 2H), 3.39-3.49 (m, 2H), 3.70 (s, 2H), 3.95 (s, 3H), 4.13-4.26 (m, 2H), 6.31 (d, J=5.4 Hz, 1H), 7.04-7.41 (m, 7H), 7.35 (s, 1H), 7.48 (s, 1H), 7.57-7.63 (m, 1H), 8.21 (s, 1H), 8.40 (d, J=5.4 Hz, 1H), 10.69 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 617 (M⁺+1)

Example 309 1-(3-Fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea

¹H-NMR (CDCl₃:CD₃OD=10:1, 400 MHz): δ 1.75-3.00 (m, 9H), 3.30-3.72 (m, 6H), 3.76 (s, 2H), 4.04 (s, 3H), 4.34 (t, J=5.4 Hz, 2H), 6.50 (d, J=5.4 Hz, 1H), 7.24-7.46 (m, 8H), 7.58 (s, 1H), 7.96 (dd, J=2.4, 11.7 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=633 (M+1)

Example 310 1-(3-Fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.00-3.20 (m, 15H), 3.73 (s, 2H), 4.02 (s, 3H), 4.27 (t, J=6.1 Hz, 2H), 6.45 (d, J=5.4 Hz, 1H), 7.08-7.17 (m, 2H), 2.22-7.44 (m, 5H), 7.54 (s, 1H), 7.94 (dd, J=2.4, 11.5 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=651 (M+1)

Example 311 1-(2-Fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenyl-acetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.22-2.19 (m, 9H), 2.49-2.69 (m, 2H), 2.87-3.07 (m, 2H), 3.41-3.50 (m, 2H), 3.70 (s, 2H), 3.93 (s, 3H), 4.17-4.21 (m, 2H), 6.43 (d, J=5.3 Hz, 1H), 6.89-6.94 (m, 2H), 7.19-7.45 (m, 5H), 7.36 (s, 1H), 7.40 (s, 1H), 7.65 (s, 1H), 8.13 (t, J=8.8 Hz, 1H), 8.43 (d, J=5.3 Hz, 1H), 10.66 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 617 (M⁺+1)

Example 312 1-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea

¹H-NMR (DMSO-d₆, 400 MHz): δ 3.17-3.40 (m, 6H), 3.50-3.65 (m, 4H), 3.83 (s, 2H), 3.94 (s, 3H), 4.00-4.13 (m, 2H), 4.13-4.26 (m, 1H), 4.90-5.00 (m, 1H), 6.48 (d, J=5.1 Hz, 1H), 7.17-7.57 (m, 9H), 7.93-8.10 (m, 1H), 8.49 (d, J=5.1 Hz, 1H), 11.81 (s, 1H), 12.50 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 621 (M+1)⁺

Example 314 1-[2-(2-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.48-2.54 (m, 2H), 2.57-2.73 (m, 4H), 3.70-3.79 (m, 4H), 3.90 (s, 2H), 4.02 (s, 3H), 4.15-4.32 (m, 3H), 6.45 (d, J=5.4 Hz, 1H), 7.32-7.43 (m, 5H), 7.45 (s, 1H), 7.47-7.52 (m, 1H), 7.54 (s, 1H), 7.95 (dd, J=2.6, 11.6 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.69 (s, 1H), 12.43 (s, 1H)

ESI-MS: m/z=655 (M+1)

Example 315 1-{3-Fluoro-4-[(7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.49-2.56 (m, 2H), 2.61-2.66 (m, 2H), 2.67-2.74 (m, 2H), 3.72-3.81 (m, 6H), 4.02 (s, 3H), 4.16-4.24 (m, 2H), 4.26-4.33 (m, 1H), 6.45 (d, J=5.4 Hz, 1H), 7.14-7.42 (m, 6H), 7.46 (s, 1H), 7.54 (s, 1H), 7.94 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.73 (s, 1H), 12.42 (s, 1H)

ESI-MS: m/z=639 (M+1)

Example 316 1-[2-(2-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.40-1.52 (m, 2H), 1.55-1.70 (m, 4H), 2.62-2.93 (m, 6H), 3.63 (s, 2H), 3.96 (s, 3H), 3.98-4.22 (m, 3H), 6.50 (d, J=5.1 Hz, 1H), 7.27-7.51 (m, 6H), 7.54 (s, 1H), 7.82 (dd, J=2.2, 11.9 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 9.95 (s, 1H), 11.91 (br, 1H), 12.45 (br, 1H)

ESI-MS: m/z=653 (M+1)

Example 317 1-[2-(2-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.84-1.92 (m, 4H), 3.01-3.36 (m, 6H), 3.63 (s, 2H), 3.97 (s, 3H), 4.10-4.26 (m, 3H), 6.51 (d, J=5.1 Hz, 1H), 7.27-7.51 (m, 6H), 7.55 (s, 1H), 7.84 (dd, J=2.4, 12.2 Hz, 1H), 8.51 (d, J=5.1 Hz, 1H), 9.96 (s, 1H), 11.91 (br, 1H), 12.45 (br, 1H)

ESI-MS: m/z=639 (M+1)

Example 318 1-(3-Fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl)-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.32-1.60 (m, 6H), 2.50-2.68 (m, 6H), 3.63 (s, 2H), 3.95 (s, 3H), 4.04-4.20 (m, 3H), 6.49 (d, J=5.1 Hz, 1H), 7.12-7.24 (m, 2H), 2.26-7.57 (m, 6H), 8.02 (dd, J=2.2, 12.2 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 11.87 (br, 1H), 12.42 (br, 1H)

ESI-MS: m/z=637 (M+1)

Example 319 1-{3-Fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.78-1.85 (m, 4H), 2.80-3.15 (m, 4H), 3.32-3.35 (m, 2H), 3.63 (s, 2H), 3.96 (s, 3H), 4.08-4.20 (m, 3H), 6.50 (d, J=5.4 Hz, 1H), 7.13-7.46 (m, 6H), 7.54 (s, 1H), 7.83 (dd, J=2.7, 12.9 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H), 9.93 (s, 1H), 11.88 (br, 1H), 12.43 (br, 1H)

ESI-MS: m/z=623 (M+1)

Example 320 1-[2-(3-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (DMSO, 400 MHz): δ 3.34-3, 43 (m, 6H), 3.59-3.64 (m, 4H), 3.87 (s, 2H), 3.95 (s, 3H), 4.06-4.14 (m, 2H), 4.19 (d, J=6.6 Hz, 1H), 6.49 (d, J=5.4 Hz, 1H), 7.26-7.57 (m, 8H), 8.01 (dd, J=2.6, 12.4 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 11.83 (s, 1H), 12.43 (s, 1H)

ESI-MS: m/z=655 (M+1)

Example 321 1-[2-(3-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.37-1.61 (m, 6H), 2.50-2.55 (m, 6H), 3.62 (s, 2H), 3.95 (s, 3H), 4.05-4.21 (m, 3H), 6.49 (d, J=5.1 Hz, 1H), 7.21-7.55 (m, 7H), 7.32 (dd, J=2.4, 12.4 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 9.93 (s, 1H), 11.79 (br, 1H), 12.42 (br, 1H)

ESI-MS: m/z=655 (M+1)

Example 322 1-[2-(3-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.82-1.90 (m, 4H), 2.90-3.50 (m, 6H), 3.62 (s, 2H), 3.97 (s, 3H), 4.09-4.25 (m, 3H), 6.51 (d, J=5.1 Hz, 1H), 7.22-7.57 (m, 7H), 7.82 (dd, J=2.2, 12.0 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 9.94 (s, 1H), 11.83 (br, 1H), 12.44 (br, 1H)

Example 323 1-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 3.33-3.41 (m, 6H), 3.57-3.63 (m, 4H), 3.87 (s, 2H), 3.95 (s, 3H), 4.04-4.22 (m, 3H), 6.48 (d, J=5.4 Hz, 1H), 7.05-7.23 (m, 3H), 7.36-7.56 (m, 5H), 8.01 (dd, J=2.1, 12.3 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 11.83 (s, 1H), 12.45 (s, 1H)

ESI-MS: m/z=639 (M+1)

Example 324 1-{3-Fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.38-1.48 (m, 2H), 1.52-1.64 (m, 4H), 2.51-2.79 (m, 6H), 3.61 (s, 2H), 3.95 (s, 3H), 4.06-4.21 (m, 3H), 6.49 (d, J=5.1 Hz, 1H), 7.06-7.56 (m, 7H), 8.02 (dd, J=2.4, 12.4 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 9.96 (s, 1H), 11.83 (br, 1H), 12.45 (br, 1H)

ESI-MS: m/z=637 (M+1)

Example 325 1-{3-Fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.84-1.92 (m, 4H), 3.00-3.40 (m, 6H), 3.88 (s, 2H), 3.96 (s, 3H), 4.10-4.25 (m, 3H), 6.50 (d, J=5.1 Hz, 1H), 7.06-7.58 (m, 7H), 8.01 (dd, J=2.4, 12.2 Hz, 1H), 8.51 (d, J=5.1 Hz, 1H), 9.97 (s, 1H), 11.83 (br, 1H), 12.45 (br, 1H)

ESI-MS: m/z=623 (M+1)

Example 326 1-[2-(4-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 2.53-2.73 (m, 6H), 3.72 (s, 2H), 3.73-3.78 (m, 4H), 4.03 (s, 3H), 4.14-4.34 (m, 3H), 6.47 (d, J=5.4 Hz, 1H), 7.20-7.34 (m, 4H), 7.37-7.42 (m, 2H), 7.44 (s, 1H), 7.56 (s, 1H), 7.94 (dd, J=2.6, 11.6 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=655 (M+1)

Example 327 1-[2-(4-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.39-1.43 (m, 2H), 1.57-1.66 (m, 4H), 2.55-2.72 (m, 6H), 3.61 (s, 2H), 3.95 (s, 3H), 4.06-4.09 (m, 2H), 4.24-4.31 (m, 1H), 6.39 (d, J=5.4 Hz, 1H), 7.10-7.30 (m, 7H), 7.43-7.49 (m, 1H), 7.48 (s, 1H), 8.34 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=653 (M+1)

Example 328 1-[2-(4-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 2.01-2.08 (m, 4H), 3.3.30-3.35 (m, 6H), 3.65 (s, 2H), 3.95 (s, 3H), 4.06-4.20 (m, 2H), 4.35-4.45 (m, 1H), 6.41 (d, J=5.4 Hz, 1H), 7.12-7.32 (m, 7H), 7.49 (s, 1H), 7.88 (dd, J=2.4, 11.7 Hz, 1H), 8.37 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=639 (M+1)

Example 329 1-{3-Fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.43-1.55 (m, 2H), 1.62-1.78 (m, 4H), 2.48-2.90 (m, 6H), 3.63 (s, 2H), 3.95 (s, 3H), 4.05-4.18 (m, 2H), 4.32-4.43 (m, 1H), 6.38 (d, J=5.4 Hz, 1H), 6.83-7.03 (m, 1H), 7.15-7.30 (m, 6H), 7.32 (s, 1H), 8.48 (s, 1H), 8.37 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=637 (M-1-1)

Example 330 1-{3-Fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 2.09-2.15 (m, 4H), 3.33-3.43 (m, 6H), 3.70 (s, 2H), 4.04 (s, 3H), 4.14-4.27 (m, 2H), 4.46-4.53 (m, 1H), 6.49 (d, J=5.4 Hz, 1H), 6.96-7.13 (m, 2H), 7.22-7.40 (m, 5H), 7.58 (s, 1H), 7.96 (dd, J=2.4, 11.5 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=623 (M+1)

Example 331 1-{3-Fluoro-4-[(7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.50-1.60 (m, 2H), 1.76-1.84 (m, 4H), 2.93-3.07 (m, 6H), 3.70 (s, 2H), 3.97 (s, 3H), 4.08-4.19 (m, 2H), 4.43-4.51 (m, 1H), 6.42 (d, J=5.4 Hz, 1H), 7.18-7.40 (m, 8H), 7.51 (s, 1H), 7.90 (dd, J=2.3, 11.6 Hz, 1H) 8.40 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=619 (M+1)

Example 332 1-{3-Fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenyl-acetyl)-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 2.03-2.11 (m, 4H), 3.20-3.40 (m, 6H), 3.70 (s, 2H), 3.98 (s, 3H), 4.09-4.22 (m, 2H), 4.43-4.51 (m, 1H), 6.43 (d, J=5.0 Hz, 1H), 7.19-7.40 (m, 8H), 7.52 (s, 1H), 7.90 (dd, J=2.6, 11.7 Hz, 1H), 8.41 (d, J=5.0 Hz, 1H)

ESI-MS: m/z=605 (M+1)

Example 333 1-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.36 (s, 3H), 2.70-2.90 (m, 6H), 3.77-3.87 (m, 6H), 4.02 (s, 3H), 4.20-4.24 (m, 2H), 4.40-4.47 (m, 1H), 6.49 (d, J=5.4 Hz, 1H), 7.16-7.32 (m, 5H), 7.42 (d, J=9.0 Hz, 1H), 7.55 (s, 1H), 7.62 (s, 1H), 7.97 (dd, J=2.4, 11.7 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.55 (s, 1H), 12.54 (s, 1H)

ESI-MS: m/z=635 (M+1)

Example 334 1-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 3H), 2.60-2.85 (m, 6H), 3.72 (s, 2H), 3.77-3.83 (m, 4H), 4.02 (s, 3H), 4.22 (d, J=5.1 Hz, 2H), 4.34-4.42 (m, 1H), 6.49 (d, J=5.4 Hz, 1H), 7.09-7.35 (m, 5H), 7.41 (d, J=9.0 Hz, 1H), 7.54 (s, 1H), 7.55 (s, 1H), 7.95 (dd, J=2.6, 11.6 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.57 (s, 1H), 12.52 (s, 1H)

ESI-MS: m/z=635 (M+1)

Example 335 1-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.37 (s, 3H), 2.55-2.79 (m, 6H), 3.70-3.80 (m, 6H), 4.01 (s, 3H), 4.19-4.23 (m, 2H), 4.31-4.38 (m, 1H), 6.46 (d, J=5.4 Hz, 1H), 7.10-7.28 (m, 5H), 7.40 (d, J=9.0 Hz, 1H), 7.51 (s, 1H), 7.56 (s, 1H), 7.93 (dd, J=2.4, 11.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.84 (s, 1H), 12.54 (s, 1H)

ESI-MS: m/z=635 (M+1)

Example 336 1-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 2.43-2.65 (m, 6H), 3.62-3.72 (m, 4H), 3.67 (s, 2H), 3.94 (s, 3H), 4.09-4.25 (m, 3H), 6.33 (d, J=5.4 Hz, 1H), 6.91-7.24 (m, 6H), 7.38 (s, 1H), 7.48 (s, 1H), 7.60-7.64 (m, 1H), 8.41 (d, J=5.4 Hz, 1H), 8.88 (s, 1H), 10.62 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 623 (M⁺+1)

Example 337 1-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenyl-acetyl)-urea

¹H-NMR (CDCl₃, 400 MHz): δ 2.44-2.65 (m, 6H), 3.68-3.76 (m, 4H), 3.69 (s, 2H), 3.94 (s, 3H), 4.08-4.23 (m, 3H), 6.32 (d, J=5.1 Hz, 1H), 7.11-7.35 (m, 7H), 7.39 (s, 1H), 7.49 (s, 1H), 7.60-7.63 (m, 1H), 8.41 (m, d, J=5.1 Hz, 1H), 8.60 (s, 1H), 10.64 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 605 (M⁺+1)

Pharmacological Test Example 1 Measurement (1) of Inhibitory Activity Against Met-Autophosphorylation Using ELISA Method

Human epidermal cancer cells A431 were cultured in an RPMI 1640 medium containing 10% fetal calf serum (purchased from GIBCO BRL) within a 5% carbon dioxide incubator until 50 to 90% confluent. Cells were cultured with RPMI medium containing 0.1% fetal calf serum in 96-well flat-bottom plate in an amount of 3×10⁴ per well, and were incubated at 37° C. overnight. The medium was then replaced by a fresh RPMI medium containing 0.1% fetal calf serum. A solution of the test compound in dimethyl sulfoxide was added to each well, and the cells were incubated at 37° C. for additional one hr. A human recombinant hepatocyte growth factor (hereinafter abbreviated to “HGF”) was added to a final concentration of 50 ng/ml, and the stimulation of cells was carried out at 37° C. for 5 min. The medium was removed, the cells were washed with phosphate buffered saline (pH 7.4), and 50 μl of lysis buffer (20 mM HEPES (pH 7.4), 150 mM NaCl, 0.2% Triton X-100, 10% glycerol, 5 mM sodium orthovanadylate, 5 mM disodium ethylenediaminetetraacetate, and 2 mM Na₄P₂O₇) was then added thereto. The mixture was shaken at 4° C. for 2 hr to prepare a cell extract.

Separately, phosphate buffered saline (50 μl, pH 7.4) containing 5 μg/ml of anti-phospho-tyrosine antibody (PY20; purchased from Transduction Laboratories) was added to a microplate for ELISA (Maxisorp; purchased from NUNC), followed by gentle agitation at 4° C. overnight to coat the surface of the wells with the antibody. After washing of the plate, 300 μl of a blocking solution was added, followed by gentle agitation at room temperature for 2 hr to perform blocking. After washing, the whole quantity of the cell extract was transferred to the wells, and the plate was then allowed to incubate at 4° C. overnight. After washing, an anti-HGF receptor antibody (h-Met (C-12), purchased from Santa Cruz Biotechnology) was allowed to react at room temperature for one hr, and, after washing, a peroxidase-labeled anti-rabbit Ig antibody (purchased from Amersham) was allowed to react at room temperature for one hr. After washing, a chromophoric substrate for peroxidase (purchased from Sumitomo Bakelite Co., Ltd.) was added thereto to initiate a reaction. After a suitable level of color development, a reaction termination solution was added to stop the reaction, and the absorbance at 450 nm was measured with a microplate reader. The met-phosphorylation inhibitory activity for each well was determined by presuming the absorbance with the addition of HGF and the vehicle to compounds to be 0% met-phosphorylation inhibitory activity and the absorbance with the addition of the vehicle to compounds and without HGF to be 100% met phosphorylation inhibitory activity. The concentration of the test compound was varied on several levels, the inhibition (%) of met-phosphorylation was determined for each case, and the concentration of the test compound necessary for inhibiting 50% of met phosphorylation (IC₅₀) was calculated. The results are shown in Table 1.

TABLE 1 Example No. IC₅₀, μM 1 0.0087 2 0.0118 3 0.0197 11 0.0581

Pharmacological Test Example 2 Measurement (2) of Inhibitory Activity Against Met-Autophosphorylation Using ELISA Method

Human gastric cancer cells MKN45 were maintained in RPMI 1640 medium containing 10% fetal calf serum (purchased from GIBCO BRL) in 5% carbon dioxide incubator until 50 to 90% confluent. Cells were cultured with RPMI medium containing 0.1% fetal calf serum in 96-well flat-bottom plate in an amount of 3×10⁴ per well, and were incubated at 37° C. overnight. The medium was then replaced by a fresh RPMI medium containing 0.1% fetal calf serum. A solution of the test compound in dimethyl sulfoxide was added to each well, and the incuvation was continued at 37° C. for additional one hr. The medium was removed, the cells were washed with phosphate buffered saline (pH 7.4), and 50 μl of a lysis buffer (20 mM HEPES (pH 7.4), 150 mM NaCl, 0.2% Triton X-100, 10% glycerol, 5 mM sodium orthovanadylate, 5 mM disodium ethylenediaminetetraacetate, and 2 mM Na₄P₂O₇) was then added thereto. The mixture was shaken at 4° C. for 2 hr to prepare a cell extract.

Separately, phosphate buffered saline (50 μl, pH 7.4) containing 5 μg/ml of anti-phospho-tyrosine antibody (PY20; purchased from Transduction Laboratories) was added to a microplate for ELISA (Maxisorp; purchased from NUNC), followed by gentle agitation at 4° C. overnight to coat the surface of the wells with the antibody. After washing of the plate, 300 μl of a blocking solution was added, followed by gentle agitation at room temperature for 2 hr to perform blocking. After washing, the whole quantity of the cell extract was transferred to the wells, and the plate was then allowed to stand at 4° C. overnight. After washing, an anti-HGF receptor antibody (h-Met (C-12), purchased from Santa Cruz Biotechnology) was allowed to react at room temperature for one hr, and, after washing, a peroxidase-labeled anti-rabbit Ig antibody (purchased from Amersham) was allowed to react at room temperature for one hr. After washing, a chromophoric substrate for peroxidase (purchased from Sumitomo Bakelite Co., Ltd.) was added thereto to initiate a reaction. After a suitable level of color development, a reaction termination solution was added to stop the reaction, and the absorbance at 450 nm was measured with a microplate reader. The met phosphorylation activity for each well was determined by presuming the absorbance with the addition of the vehicle to be 100% met phosphorylation activity and the absorbance with the addition of a largely excessive amount of positive control (compound 1, 1000 nM) to be 0% met phosphorylation activity. The concentration of the test compound was varied on several levels, the inhibition (%) of met-phosphorylation was determined for each case, and the concentration of the test compound necessary for inhibiting 50% of met phosphorylation (IC₅₀) was calculated. The results are shown in Table 2.

TABLE 2 Ex. No. IC₅₀, μM 1 0.0112 2 0.0181 3 0.0304 4 0.0750 5 0.0189 6 0.0316 7 0.2922 8 0.2976 9 0.0364 10 0.1459 11 0.0202 12 0.1990 13 0.1411 14 0.2909 15 0.3017 16 0.0328 17 0.0307 18 0.1496 19 0.1040 20 0.0318 21 0.1876 22 0.0246 23 0.0263 24 0.0277 25 0.1401 26 0.1256 27 0.0800 28 0.1624 29 0.0371 30 0.0351 31 0.0341 32 0.1709 33 0.0618 34 0.0463 35 0.0414 36 0.1982 37 0.0584 38 0.0291 39 0.1145 40 0.2421 41 0.2807 42 0.1899 43 0.1674 44 0.2915 45 0.2071 46 0.2290 47 0.2153 48 0.2240 49 0.0514 50 0.2355 51 0.2035 52 0.1706 53 0.0374 54 0.0261 55 0.2449 56 0.1400 57 0.1320 58 0.0270 59 0.1930 60 0.0370 61 0.1130 62 0.0920 63 0.0244 64 0.1405 65 0.0663 66 0.0792 67 0.0197 68 0.1944 69 0.0044 70 0.0153 71 0.0299 72 0.0279 73 0.0281 74 0.1825 75 0.0336 76 0.0517 77 0.1776 78 0.0663 79 0.1454 80 0.0302 81 0.0277 82 0.0743 83 0.0391 84 0.0400 85 0.0488 86 0.0235 87 0.1983 88 0.0492 89 0.0526 90 0.0281 91 0.0401 92 0.1480 93 0.1215 94 0.0307 95 0.0413 96 0.1706 97 0.0376 98 0.0278 99 0.0256 100 0.0308 101 0.0444 102 0.0918 103 2.7714 104 0.3442 105 0.1037 106 0.0427 107 0.3450 108 2.0800 109 1.4756 110 2.3751 111 1.8118 112 1.7334 113 0.6535 114 0.4850 115 0.3592 116 0.3440 117 1.3037 118 0.2114 119 0.4420 120 1.5748 121 0.3380 122 0.3026 123 2.0088 124 0.2643 125 0.2933 126 0.3295 127 0.3189 128 0.2847 129 1.0060 130 2.1555 131 2.3731 132 0.2683 133 0.2610 134 0.2319 135 0.2260 136 0.3417 137 0.2707 138 0.2843 139 0.2432 140 0.2288 141 0.3361 142 0.2847 143 3.5910 144 0.6990 145 0.3640 146 1.2100 147 1.1660 148 2.4790 149 0.2360 150 1.2780 151 0.2561 152 0.2475 153 0.2320 154 0.8760 155 0.9820 156 0.3730 157 0.4820 158 0.4650 159 0.5850 160 1.6327 161 0.2460 162 0.2096 163 0.2018 164 0.2417 165 0.4950 166 0.3183 167 0.2586 168 0.3056 169 0.2759 170 0.2736 171 0.2817 172 0.4228 173 0.2217 174 0.2522 175 0.9552 176 0.2211 177 0.2672 178 0.2680 179 0.2613 180 2.5610 181 0.2431 182 0.2559 183 0.2238 184 0.2677 185 0.2477 186 0.2340 187 0.2575 188 0.2525 189 0.2323 190 0.2237 191 0.9767 192 0.6874 193 0.4442 194 0.3188 195 0.2914 196 0.3219 197 0.2842 198 0.2938 199 0.2415 200 0.3052 201 0.2255 202 0.6416 203 0.2813 204 0.3209 205 0.2651 206 0.4436 207 0.2998 208 0.2580 209 0.9285 210 0.2277 211 0.2521 212 0.3787 213 2.4266 214 2.5273 215 1.9770 216 0.2278 217 0.3331 218 0.4793 219 0.7359 220 0.2967 221 0.2212 222 0.2014 223 0.2680 224 0.3160 225 0.2814 226 3.2308 227 4.3638 228 0.3936 229 0.2730 230 0.3403 231 0.3288 232 0.2557 233 0.3217 234 0.4568 235 0.2146 236 0.2351 237 1.4669 238 4.0204 239 1.5818 240 2.7412 241 3.3169 242 0.8512 243 3.0098 244 0.3419 245 0.3082 246 2.9114 247 0.6502 248 0.9569 249 0.5256 250 0.4474 251 0.3862 252 0.3005 253 1.3400 254 0.3655 255 0.2601 256 0.2808 257 0.2859 258 0.3574 259 0.6143 260 2.2325 261 0.3426 262 0.2689 263 0.4835 264 0.3472 265 0.2589 266 0.1806 267 0.1091 268 0.0228 269 0.0125 270 0.0267 271 0.0391 272 0.0336 273 0.0240 275 0.0230 276 0.0190 277 0.0204 278 0.0251 279 0.0204 282 0.0166 283 0.0146 284 0.0150 285 0.0753 286 0.0293 287 0.0225 288 0.0226 289 0.0238 291 0.0195 292 0.0203 293 0.0211 294 0.0230 295 0.0241 296 0.0197 297 0.0532 298 0.0890 299 0.0435 300 0.0224 301 0.0611 302 0.0231 303 0.0267 304 0.0659 305 0.0214 306 0.0339 307 0.0574 308 0.0214 309 0.0201 310 0.0211 311 0.0185 312 0.0191 313 0.0211 314 0.0232 315 0.0210 316 0.1882 317 0.0422 318 0.0283 319 0.1267 320 0.0140 321 0.1248 322 0.0426 323 <0.0100 324 0.0234 325 0.0185 326 0.0131 327 0.7978 328 0.0432 329 0.0518 330 0.0206 331 0.0220 332 0.0142 333 0.0211 334 0.0227 335 0.0236 336 0.0328 337 0.0220

Pharmacological Test Example 3 Tumor Growth Inhibitory Activity Against Human Gastric Cancer Cells (MKN 45)

Human gastric cancer cells (MKN 45) were transplanted into nude mice. When the tumor volume became about 100 to 200 mm³, the mice were grouped so that the groups each consisted of five mice and had an even average tumor volume. The test compound suspended in 0.5% methylcellulose was orally administered twice a day for 5 days.

Only 0.5% methylcellulose was administered to the control group in the manner as in the test groups. The tumor growth inhibition rate (TGIR) was calculated as follows: The tumor growth inhibition rate (TGIR)=(1−TX/CX)×100 wherein CX represents the relative tumor volume at day X for the control group when the tumor volume at the day of the start of the administration was presumed to be 1; and TX represents the relative tumor volume for test compound administration groups.

The tumor growth inhibition rate for representative examples of a group of compounds according to the present invention is shown in Table 3.

TABLE 3 Dose, mg/kg/time TGIR, % Example 1 10 21 30 47 100 54 Example 2 10 31 30 65 Example 3 10 24 30 52 Example 11 10 23 30 52 Example 268 30 81

Pharmacological Test Example 4 Tumor Growth Inhibitory Activity Against Human Brain Tumor Cells (U87MG)

Human brain tumor cells (U87MG) were transplanted into nude mice. When the tumor volume became about 100 to 200 mm³, the mice were grouped so that the groups each consisted of five mice and had an even average tumor volume. The test compound suspended in 0.5% methylcellulose was orally administered twice a day for 5 days.

Only 0.5% methylcellulose was administered to the control group in the manner as in the test groups. The tumor growth inhibition rate (TGIR) was calculated as follows: The tumor growth inhibition rate (TGIR)=(1−TX/CX)×100 wherein CX represents the relative tumor volume at day X for the control group when the tumor volume at the day of the start of the administration was presumed to be 1; and TX represents the relative tumor volume for test compound administration groups.

The tumor growth inhibition rate for representative examples of a group of compounds according to the present invention is shown in Table 4.

TABLE 4 Dose, mg/kg/time TGIR, % Example 1 30 42 100 70 Example 2 10 38 30 61 Example 3 30 51 100 60

Pharmacological Test Example 5 Tumor Growth Inhibitory Activity Against Various Human Tumor Cells

Human gastric cancer cells (MKN 45) (obtained from RIKEN), human brain tumor cells (U87MG) (obtained from ATCC), human pancreatic cancer cells (KP4) (obtained from RIKEN), human pancreatic cancer cells (SUIT-2) (obtained from National Kyushu Cancer Center), and human signet-ring type gastric cancer cells (NUGC-4) (obtained from RIKEN), or human lung cancer cells (LC6) (obtained from Central Laboratories for Experimental Animals) were transplanted into nude mice. When the tumor volume became about 100 mm³, the mice were grouped so that the groups each consisted of four or five mice and had an even average tumor volume. The test compound suspended in 0.5% methylcellulose was orally administered once or twice a day for 5 days. Only 0.5% methylcellulose was administered to the control group in the manner as in the test groups. Alternatively, the test compound dissolved in physiological saline (with a 1 N aqueous hydrochloric acid solution added thereto) was intraveneously injected once a day for 5 days, and only physiological saline (with a 1 N aqueous hydrochloric acid solution added thereto) was administered to the control group in the same manner as in the test groups. The tumor growth inhibition rate (TGIR) was calculated as follows: The tumor growth inhibition rate (TGIR)=(1−TX/CX)×100 wherein CX represents the relative tumor volume at the 5^(th) day for the control group when the tumor volume at the day of the start of the administration was presumed to be 1; and TX represents the relative tumor volume for test compound administration groups.

The tumor growth inhibition rate for representative examples of a group of compounds according to the present invention is shown in Table 5.

TABLE 5 Ex. Administration Dose, mg/kg × No. Tumor method number of times TGIR, % 1 LC6 Oral 30 × 2 26 2 NUGC-4 Oral 30 × 2 75 2 LC6 Oral 30 × 2 27 2 KP-4 Oral 30 × 2 54 3 NUGC-4 Oral 30 × 2 71 3 LC6 Oral 30 × 2 18 3 KP-4 Oral 30 × 2 31 11 MKN45 Oral 30 × 2 63 11 U87MG Oral 30 × 2 62 11 LC6 Oral 30 × 2 26 46 MKN45 Oral 25 × 1 38 268 MKN45 i.v. injection 10 × 1 52 268 LC6 Oral 30 × 2 35 268 U87MG Oral 30 × 2 74 277 MKN45 Oral 30 × 2 17 282 MKN45 Oral 30 × 2 13 282 MKN45 i.v. injection 10 × 1 31 285 MKN45 Oral 30 × 2 66 285 LC6 Oral 30 × 2 48 286 MKN45 Oral 30 × 2 64 286 LC6 Oral 30 × 2 37 286 U87MG Oral 30 × 2 66 288 MKN45 Oral 30 × 2 64 299 MKN45 Oral 25 × 1 14 312 MKN45 Oral 30 × 2 75 313 MKN45 Oral 12.5 × 1  37 313 MKN45 Oral 25 × 1 73 313 MKN45 Oral 50 × 1 78 313 MKN45 i.v. injection 10 × 1 68 313 SUIT-2 Oral 25 × 1 28 313 KP-4 Oral 12.5 × 1  34 313 KP-4 Oral 25 × 1 45 313 KP-4 Oral 50 × 1 48 314 MKN45 Oral 30 × 2 38 315 MKN45 Oral 30 × 2 36 320 MKN45 Oral 30 × 2 20 323 MKN45 Oral 30 × 2 34 326 MKN45 Oral 30 × 2 17 331 MKN45 Oral 30 × 2 40 332 MKN45 Oral 30 × 2 14 333 MKN45 Oral 30 × 2 75 334 MKN45 Oral 30 × 2 65 

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

wherein X represents CH or N; Z represents O or S; L represents O; M represents (1-1) —CR¹⁰R¹¹— wherein R¹⁰ and R¹¹ may be the same or different, and each represents a hydrogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, or (1-2) —NR¹²—, wherein R¹² represents a hydrogen atom or C₁₋₄ alkyl; R¹, R², and R³ may be the same or different, and each represents (2-1) a hydrogen atom, (2-2) hydroxyl, (2-3) a halogen atom, (2-4) nitro, (2-5) —NR²⁰R²¹, wherein R²⁰ and R²¹ may be the same or different, and each represents a hydrogen atom or C₁₋₆ alkyl optionally substituted by hydroxyl or C₁₋₆ alkoxy, (2-6) C₁₋₆ alkyl, (2-7) C₂₋₆ alkenyl, (2-8) C₂₋₆ alkynyl, or (2-9) C₁₋₆ alkoxy; wherein the (2-6) C₁₋₆ alkyl, the (2-7) C₂₋₆ alkenyl, the (2-8) C₂₋₆ alkynyl, and the (2-9) C₁₋₆ alkoxy are optionally substituted by (3-1) hydroxyl, (3-2) a halogen atom, (3-3) C₁₋₆ alkoxy, (3-4) C₁₋₆ alkylcarbonyl, (3-5) C₁₋₆ alkoxy carbonyl, (3-6) —NR²²R²³ wherein R²² and R²³ may be the same or different, and each represents a hydrogen atom or C₁₋₆ alkyl optionally substituted by hydroxyl or C₁₋₆ alkoxy, or (3-7) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted by hydroxyl or C₁₋₆ alkoxy; R⁵, R⁶, R⁷, and R⁸ may be the same or different, and each represents (4-1) a hydrogen atom, (4-2) a halogen atom, (4-3) C₁₋₄ alkyl, or (4-4) C₁₋₄ alkoxy; and R⁹ represents (5-1) C₁₋₆ alkyl wherein one or more hydrogen atoms on the C₁₋₆ alkyl are optionally substituted by (6-1) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, (6-2) -T-R¹⁵, wherein T represents O, S, or NH, and R¹⁵ represents C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or (6-3) —NR¹⁶R¹⁷ wherein R¹⁶ and R¹⁷ may be the same or different, and each represents C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; (5-2) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; or (5-3) —NR¹⁸R¹⁹, wherein R¹⁸ and R¹⁹ may be the same or different, and each represents (7-1) a hydrogen atom, (7-2) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or (7-3) C₁₋₆ alkyl optionally substituted by C₁₋₆ alkoxy, C₁₋₆ alkylthio, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, provided that, when X represents CH; Z represents O; L represents O; M represents —NH—; R¹, R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom; and R² and R³ represent methoxy, R⁹ represents neither phenyl, ethoxy, nor pyridin-2-yl.
 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein Z is O.
 3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R¹ is a hydrogen atom.
 4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R² is C₁₋₆ alkoxy.
 5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R² is methoxy.
 6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R³ is (8-1) hydroxyl, or (8-2) C₁₋₆ alkoxy wherein the C₁₋₆ alkoxy is optionally substituted by (9-1) hydroxyl, (9-2) a halogen atom, (9-3) —NR²²R²³ wherein R²² and R²³ have the same meanings as defined above, or (9-4) a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl wherein the C₁₋₆ alkyl is optionally substituted by hydroxyl or C₁₋₆ alkoxy.
 7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R³ is (10-1) hydroxyl, or (10-2) C₁₋₄ alkoxy, wherein the C₁₋₄ alkoxy is optionally substituted by (11-1) hydroxyl, (11-2) a halogen atom, (11-3) —NR²²R²³ wherein R²² and R²³ have the same meanings as defined above, or (11-4) a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl wherein the C₁₋₆ alkyl is optionally substituted by hydroxyl or C₁₋₆ alkoxy.
 8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R³ is methoxy.
 9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein M is —NR¹²— wherein R¹² has the same meaning as defined above.
 10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein M is —CR¹⁰R¹¹— and wherein R¹⁰ and R¹¹ have the same meanings as defined above.
 11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R⁹ is C₁₋₆ alkyl wherein one or more hydrogen atoms on the C₁₋₆ alkyl are optionally substituted by (12-1) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, (12-2) -T-R¹⁵, wherein T and R¹⁵ have the same meanings as defined above, or (12-3) —NR¹⁶R¹⁷, wherein R¹⁶ and R¹⁷ have the same meanings as defined above.
 12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R⁹ is —CH₂—R²⁴ wherein R²⁴ represents a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, or a halogen atom.
 13. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R⁹ is: (13-1) —NR²⁵R²⁶, wherein R²⁵ represents a hydrogen atom or C₁₋₄ alkyl, and R²⁶ represents (14-1) C₁₋₄ alkyl optionally substituted by a saturated or unsaturated six-membered carbocyclic group, wherein the saturated or unsaturated six-membered carbocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated six-membered carbocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated six-membered carbocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or (14-2) a saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain.
 14. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim
 1. 15. A method for inhibiting met autophosphorylation comprising administering the compound of claim 1 to a subject in need thereof.
 16. The method of claim 15, wherein said subject has a tumor or cancer whose proliferation, invasion or metastasis is mediated by an HGF-met signal. 